Quinoline inhibitors of cGMP phosphodiesterase

ABSTRACT

are useful as inhibitors of cGMP PDE especially Type  5.

RELATED INVENTIONS

[0001] This application is related to, and pursuant to 35 U.S.C. §119(e) claims the benefit of priority of U.S. application Ser. No.60/230,267, filed Sep. 2, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to quinoline compounds, to methodsof using such compounds in treating cGMP-associated conditions such aserectile dysfunction, and to pharmaceutical compositions containing suchcompounds.

BACKGROUND OF THE INVENTION

[0003] Erectile dysfunction is the inability to obtain and maintain apenile erection sufficient for sexual intercourse or other sexualexpression. A number of factors can place an individual at risk for thisdisorder, for example, trauma, pelvic surgery, hypercholesterolemia,ischemic heart disease, peripheral vascular disease, chronic renalfailure, diabetes, the use of certain medicaments including some typesof antihypertensive agents, digoxin, or the excessive use of narcotics,alcohol, tobacco, etc. Methods for treating erectile dysfunction includethe use of vacuum devices and penile implants, as well as theadministration of medicaments such as yohimbine, papaverine andapomorphine. Improved methods for treating this disorder are sought,however, as the aforementioned methods do not provide sufficientefficacy and/or are accompanied by drawbacks or side effects such aserosion, pain, priapism, or gastrointestinal discomfort.

[0004] A penile erection is dependent upon the presence of adequatelevels of cyclic guanosine 3′,5′-monophosphate (cGMP), especially incorpora cavernosa tissue. Thus, administering an inhibitor of a cGMPphosphodiesterase (cGMP PDE), particularly a selective inhibitor of cGMPPDE Type 5 (PDE 5), provides a means for achieving and maintaining anerection and therefore, for treating erectile dysfunction. SeeTrigo-Rocha et al.,“Nitric Oxide and cGMP: Mediators of PelvicNerve-Stimulated Erection in Dogs,” Am. J. Physiol., Vol. 264 (Feb.1993); Bowman et al.,“Cyclic GMP Mediates Neurogenic Relaxation in theBovine Retractor Penis Muscle,” Br. J. Pharmac., 81, 665-674 (1984); andRajfer et al.,“Nitric Oxide as a Mediator of Relaxation of the CorpusCavernosum in Response to Nonadrenergic, NoncholinergicNeurotransmission,” New England J. Med., 326, 2, 90-94 (Jan. 1992).Sildenafil, for example, has been described as a PDE 5 inhibitor usefulfor treating erectile dysfunction. See Drugs of the Future, 22, 138-143(1997).

[0005] Recent examples of other compounds claimed as PDE 5 inhibitorsinclude fused pyridazine compounds (WO 96/05176 and U.S. patentapplication Ser. No. 09/393,833), anthranilic acid derivatives (U.S.5,716,993), fused pyridopyridazine compounds (U.S. patent applicationSer. No. 09/526,162), and quinazolinone compounds (U.S. Pat. No.6,087,368).

[0006] The present invention provides compounds that are potent andselective inhibitors of cGMP PDE 5. These compounds may be employed intreating erectile dysfunction. In view of their activity, thesecompounds can also be used in treating other disorders responding to theinhibition of cGMP PDE, such as various cardiovascular disorders.

SUMMARY OF THE INVENTION

[0007] The present invention provides quinoline compounds of thefollowing formula (I) or salts thereof, for use as inhibitors of cGMPPDE, especially Type 5:

[0008] wherein:

[0009] R₂, R₆, R₇ and R₈ are independently hydrogen, halogen, alkyl,substituted alkyl, alkoxy, nitro, cyano, aryl, heteroaryl, orheterocyclo;

[0010] R₃ is—(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3;

[0011] R₄ and R₅ (i) are independently hydrogen, alkyl, substitutedalkyl, cycloalykl, substituted cycloalkyl, aryl, or heteroaryl, with theproviso that R₄ and R₅ are not both hydrogen; or (ii) taken togetherform a heterocyclo ring;

[0012] Y is selected (i) independently from —OR₉, —CO₂R₉, —CH(CO₂R₉)₂,—O(C═O)NR₁₀R₁₁ —NR₁₀R₁₁, —NR₁₀ (C═O)NR₁₁R₁₂, —CH[(C═O)NR₁₀R₁₁]₂,—(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₁₂, —S(O)_(m)R₉, —SO₂NR₁₀R₁₁, imidazole,substituted imidazole, triazole, substituted triazole, or cyano, or (ii)together with one of R₄ and R₅ to form a heterocylo ring therewith;

[0013] m is 0, 1, or 2;

[0014] R₉ is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy,cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, orpentafluorophenyl; and

[0015] R₁₀, R₁₁, and R₁₂ (i) are independently selected from hydrogen,alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl,aryl, heterocyclo, and heteroaryl; or (ii) taken together wherein R₁₀forms a three-to seven-membered heterocyclo ring with R₁₁ or R₁₂, or R₁₁forms a three- to seven-membered heterocyclo ring with R₁₂.

[0016] The invention further provides pharmaceutical compositionsadapted for use in treating cGMP-associated conditions comprising apharmaceutically acceptable diluent or carrier and at least one compoundof the formula (I) or salt thereof, wherein R₂ and R₄, R₅, R₆, R₇, Rs,R₉, R₁₀, R₁₁ and R₁₂are as defined above and R₃ is selected fromhydrogen and —(CH₂)_(z)Y with the proviso that at least one of R₂, R₃,R₆, R₇, and R₈ is not hydrogen. The invention further provides methodsfor treating cGMP-associated conditions comprising administering to amammal in need of such treatment a therapeutically-effective amount ofone or more compounds of the formula (I) or salt thereof, wherein R₂ andR₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂are as defined above and R₃ isselected from hydrogen and —(CH₂)_(z)Y, with the proviso that at leastone of R₂, R₃, R₆, R₇, and R₈ is not hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The following are definitions of terms used in thisspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification, individually or as part of another group, unlessotherwise indicated.

[0018] The term“alkyl” refers to straight or branched chain hydrocarbongroups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, aremost preferred.

[0019] The term“substituted alkyl” refers to an alkyl group as definedabove having one, two or three substituents selected from the groupconsisting of halo, amino, cyano, hydroxy, alkoxy, alkylthio,—NH(alkyl), —NH (cycloalkyl), —N(alkyl)₂, —C(═O)H, —CO₂H, —CO₂-alkyl,cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, or heterocycle.The term“substituted alkyl” also includes an alkyl group as definedabove substituted with N(substituted alkyl) or N(substituted alkyl)₂, orin other words, the groups (CH₂),NHR′ and (CH₂)_(n)NR′R″, wherein eachof R′ and R″ comprises a substituted alkyl or R′ and R″ together form aheterocyclo ring.

[0020] The term“alkoxy” refers to an alkyl group as defined above bondedthrough an oxygen (—O—). The term“alkylthio” refers to an alkyl group asdefined above bonded through a sulfur (—S—).

[0021] The term“cycloalkyl” refers to fully saturated and partiallyunsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7, carbon atomsas well as such rings having a fused aryl ring such as indan.

[0022] The term“substituted cycloalkyl” refers to such rings having one,two or three substituents, preferably one, selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo,hydroxy, cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —CO₂H,—CO₂-lower alkyl, aryl, heterocyclo, heteroaryl, keto, ═N—OH, ═N—O—loweralkyl, and a five or six membered ketal, i.e.1,3-dioxolane or1,3-dioxane.

[0023] The term“halo” refers to chloro, bromo, fluoro and iodo.

[0024] The term“aryl” refers to phenyl, 1-naphthyl and 2-naphthyl, withphenyl being preferred. The term“aryl” includes such rings having fromzero, one, two or three substituents, selected from the group consistingof alkyl, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro,cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —CO₂H,—(C═O)alkyl, —CO₂-alkyl, cycloalkyl, substituted cycloalkyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂—CO₂H,—NH—CH₂—CO₂-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,heterocyclo, and heteroaryl.

[0025] The term“heterocyclo” refers to substituted and unsubstitutednon-aromatic 3 to 7 membered monocyclic groups, 7 to 11 memberedbicyclic groups, and 10 to 15 membered tricyclic groups which have atleast one heteroatom (O, S or N) in at least one of the rings. Each ringof the heterocyclo group containing a heteroatom can contain one or twooxygen or sulfur atoms and/or from one to four nitrogen atoms providedthat the total number of heteroatoms in each ring is four or less, andfurther provided that the ring contains at least one carbon atom. Thefused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. The heterocyclogroup may be attached at any available nitrogen or carbon atom. Theheterocyclo ring may contain one, two or three substituents selectedfrom the group consisting of halo, amino, cyano, alkyl, substitutedalkyl, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, alkoxy, alkylthio,hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,—CO₂H, —CO₂-alkyl, cycloalkyl, substituted cycloalkyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂—CO₂H,—NH—CH₂—CO₂-alkyl, heterocyclo, heteroaryl, keto, ═N—OH, ═N—O-loweralkyl, and a five or six membered ketal, i.e., 1,3-dioxolane or1,3-dioxane.

[0026] Exemplary monocyclic groups include azetidinyl, pyrrolidinyl,oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1, 1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

[0027] The term“heteroaryl” refers to substituted and unsubstitutedaromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclicgroups, and 11 to 14 membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. The fused rings completing the bicyclicand tricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen atoms may optionally bequaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring. Theheteroaryl ring system may contain one, two or three substituentsselected from the group consisting of halo, amino, cyano, alkyl,substituted alkyl, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, alkoxy,alkylthio, hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy,phenylthio, —CO₂H, —CO₂-alkyl, cycloalkyl, substituted cycloalkyl,—(C═O)NH₂, —(C═O)N H(alkyl),—(C═O)NH(cycloalkyl),—(C═O)N(alkyl)₂,—NH—CH₂—CO₂H, —NH—CH₂—CO₂-alkyl,heterocylco, and heteroaryl.

[0028] Exemplary monocyclic heteroaryl groups include pyrrolyl,pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

[0029] Exemplary bicyclic heteroaryl groups include indolyl,benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

[0030] Exemplary tricyclic heteroaryl groups include carbazolyl,benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl andthe like.

[0031] The term“substituted imidazole” refers to an imidazole, anaryl-fused imidazole such as benzimidazole, or a heteroaryl-fusedimidazole such as a pyridoimidazole which contain one or twosubstituents selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro, cyano,amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl) ₂, —CO₂H,—CO₂-alkyl,cycloalkyl, substituted cycloalkyl, —(C═O)NH ₂,—(C═O)NH(alkyl),—(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂—CO₂H,—NH—CH₂—CO₂-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,heterocyclo, and heteroaryl.

[0032] The term“substituted triazole” refers to a triazole having atleast one substituent selected from the group consisting of alkyl,substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro, cyano,amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, —CO₂H, —CO₂-alkyl,cycloalkyl, substituted cycloalkyl, —(C═O)NH₂, —(C═O)NH(alkyl),—(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂—CO₂H, —NH—CH₂—CO₂-alkyl,phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, heterocyclo, andheteroaryl.

[0033] Throughout the specification, groups and substituents thereof maybe chosen to provide stable moieties and compounds.

[0034] The compounds of formula I form salts which are also within thescope of this invention. Reference to a compound of the formula I hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term“salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety,such as, but not limited to an amine or a pyridine or imidazole ring,and an acidic moiety, such as, but not limited to a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm“salt(s)” as used herein. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful, e.g., in isolation or purification stepswhich may be employed during preparation. Salts of the compounds of theformula I may be formed, for example, by reacting a compound of theformula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

[0035] The compounds of formula I which contain a basic moiety, such as,but not limited to an amine or a pyridine or imidazole ring, may formsalts with a variety of organic and inorganic acids. Exemplary acidaddition salts include acetates (such as those formed with acetic acidor trihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

[0036] The compounds of formula I which contain an acidic moiety, suchas, but not limited to a carboxylic acid, may form salts with a varietyof organic and inorganic bases. Exemplary basic salts include ammoniumsalts, alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines [formed withN,N-bis(dehydro-abietyl)ethylenediamine], N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g., methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g., benzyl and phenethylbromides), and others.

[0037] Prodrugs and solvates of the compounds of this invention are alsocontemplated herein. The term“prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, and/or a salt and/or solvate thereof. Solvates of thecompounds of formula I are preferably hydrates.

[0038] Compounds of the formula I, and salts thereof, may exist in theirtautomeric form (for example, as an amide or imino ether). All suchtautomeric forms are contemplated herein as part of the presentinvention.

[0039] All stereoisomers of the present compounds, such as those, forexample, which may exist due to asymmetric carbons on the R₂ to R₁₂substituents, including enantiomeric forms (which may exist even in theabsence of asymmetric carbons) and diastereomeric forms, arecontemplated and within the scope of this invention. Individualstereoisomers of the compounds of this invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other or other selected, stereoisomers. The chiralcenters of the present invention can have the S or R configuration asdefined by the IUPAC 1974 Recommendations.

METHODS OF PREPARATION

[0040] The compounds of the present invention may be prepared by methodssuch as those illustrated in the following Schemes I to X. Startingmaterials are commercially available or can be readily prepared by oneof ordinary skill in the art using known methods. For all of the schemesand compounds, the groups R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are asdescribed above for a compound of formula I, unless otherwise indicated.

[0041] Solvents, temperatures, pressures, and other reaction conditionsmay readily be selected by one of ordinary skill in the art. Forexample, in these schemes exemplary hydroxide sources may include sodiumhydroxide or lithium hydroxide; an exemplary reducing reagent and inertsolvent (for reducing a carboxylic acid or ester group to an alcohol)includes lithium tri-t-butoxyaluminohydride and tetrahydrofuran (THF);exemplary dehydrating/chlorinating agents include POCl₃, PCl₅, SOCl₂ oroxalyl chloride; exemplary leaving groups (LG) include triflate,mesylate, tosylate, or halide; and exemplary reagents (for converting ahydroxyl group to a leaving group) include trifluoromethanesulfonylchloride, toluenesulfonyl chloride, methanesulfonyl chloride, phosphorusoxychloride, thionyl chloride, and phosphorus pentachloride. Exemplarysolvents, as appropriate, may be selected from 1,2-dichlorobenzene,methylene chloride, dimethylformamide (DMF), alcohols, ethers, includingdiphenyl ether, tetrahydrofuran and dioxane, N,N-dimethylformamide, andacetonitrile, water, mixtures of ethers and water, and the like.

[0042] High Speed Analoging (HSA) may be employed in the preparation ofcompounds.

[0043] Compounds of formula la wherein R₃ is hydrogen can be preparedvia the decarboxylation of a compound of formula Ib in an appropriatedegassed inert solvent (e.g., 1,2-dichlorobenzene and diphenyl ether) atelevated temperature.

[0044] Compounds of formula Ib wherein R₃ is —CO₂H can be prepared bythe hydrolysis of compounds of formula Ic using a hydroxide source andappropriate solvent (e.g., water, alcohols, and mixtures of ethers andwater).

[0045] Compounds of formula Id wherein R₃ is —CH₂OH can be prepared byreducing a compound of formula Ib or Ic with an appropriate reducingreagent in an inert (reaction) solvent.

[0046] Compounds of formula Ic wherein R₃ is —CO₂R₉ can be prepared byreacting compounds of formula II with an amine of the formula NHR₄R₅.The reaction may be performed in a solvent as appropriate, such as analcohol, in the presence of an appropriate base, such as triethylamine,and typically under elevated temperatures.

[0047] Compounds of formula II can be prepared by reacting compounds offormula III with an appropriate dehydrating/chlorinating agent,typically under elevated temperatures.

[0048] Compounds of formula III can be prepared from compounds offormula IV via an intramolecular cyclization typically under elevatedtemperatures in an inert solvent, as appropriate, or in neat form.

[0049] Compounds of formula IV can be prepared by combining compounds offormula V and VI either neat or in an inert solvent as appropriate,typically under elevated temperatures.

[0050] Compounds of formula V and formula VI are either commerciallyavailable or available via methods known to one skilled in the art.

[0051] Compounds of formula le wherein R₂ is halogen and R₃ is —CH₂OHcan be prepared by reducing a compound of formula If or Ig with anappropriate reducing reagent in an inert (reaction) solvent.

[0052] Compounds of formula If wherein R₂ is halogen and R₃ is —CO₂H canbe prepared by the hydrolysis of compounds of formula Ig using ahydroxide source in appropriate solvent.

[0053] Compounds of formula Ig wherein R₂ is halogen and R₃ is —CO₂R₉(R₉is other than hydrogen) can be prepared by reacting compounds of formulaVII with an amine of the formula NHR₄R₅ (as in Scheme I for formula Ic).

[0054] Compounds of formula VII can be prepared by reacting compounds offormula VIl with an appropriate dehydrating /chlorinating agenttypically under elevated temperatures.

[0055] Compounds of formula VIII can be prepared from compounds offormula IX by a condensation with a malonate derivative using base in anappropriate solvent. Sodium alkoxides are exemplary bases and alcoholsexemplary solvents.

[0056] Compounds of formula IX are either commercially available oravailable via methods known to one skilled in the art.

[0057] Compounds of formula Ih wherein R₃ is —(CH₂) ₂OH can be preparedby reducing a compound of formula Ii with an appropriate reducingreagent in an inert solvent.

[0058] Compounds of formula Ii wherein R₃ is —CH₂CO₂H can be prepared bythe hydrolysis of compounds of formula Ij using a hydroxide source inappropriate solvent.

[0059] Compounds of formula Ij wherein R₃ is —CH₂CN can be prepared viathe displacement of the leaving group (LG) from a compound of formula Xusing an appropriate nucleophile in an inert solvent (e.g., methylenechloride). Nucleophiles may include cyanides from HCN, KCN, or NaCN, ortetrabutylammonium cyanide.

[0060] Compounds of formula X can be prepared via reaction of compoundsof formula Id or Ie with an appropriate reagent which converts thehydroxyl group to a leaving group (LG) in an inert solvent (e.g.,methylene chloride).

[0061] Compounds of formula Id or Ie wherein R₃ is —CH₂OH, can beprepared by the methods described above in Schemes I and II.

[0062] Compounds of formula Ik wherein R₃ is —(CH₂)₃OH can be preparedby reducing a compound of formula II with an appropriate reducingreagent in an inert solvent. Compounds of formula II can be prepared bydecarboxylation of compounds of formula XI at elevated temperature in aninert solvent (e.g., DMF).

[0063] Compounds of formula XI can be prepared by the hydrolysis ofcompounds of formula Im using a hydroxide source and an appropriatesolvent.

[0064] Compounds of formula Im wherein R₃ is —CH₂CH(CO₂R₉)₂ can beprepared via the displacement of the leaving group (LG) from a compoundof formula X using an appropriate nucleophile (e.g., alkyl malonate) inan inert solvent (e.g., methylene chloride).

[0065] Compounds of formula In wherein R₃ is —(CH₂)_(z)Y can be preparedvia the displacement of the leaving group (LG) from a compound offormula XI using an appropriate nucleophile in an inert solvent.Exemplary nucleophiles include alcohols of the formula HOR₉, amines ofthe formula HNR₁₀R₁₁, mercaptans of the formula HSR₉, cyanides as inScheme III, imidazole, substituted imidazoles, triazole, and substitutedtriazoles.

[0066] Compounds of formula XII can be prepared via reaction ofcompounds of formulas Id, Ie, Ih, Ik with an appropriate reagent whichconverts the hydroxyl group to a leaving group (LG) in an appropriateinert solvent.

[0067] Compounds of formulas Id (z═1), Ie (z═1), Ih (z═2), Ik (z═3) canbe prepared using the methods described above in Schemes I,II or III.

[0068] Compounds of formula Io wherein R₃ is —(CH₂),(C═O) NR₁₀R₁₁ can beprepared via the aminolysis of an active ester (AE) of formula XIIIusing an amine of the formula NHR₁₀R₁₁ in an inert solvent (e.g.,ethers, described above, and methylene chloride).

[0069] Compounds of formula Ip wherein R₃ is —(CH₂) _(z)CO₂R₉ can beprepared via the esterification of a compound of formula XIII using analcohol of the formula HOR₉, with the alcohol used as solvent or in aninert solvent such as ethers, described above, or methylene chloride.

[0070] Compounds of formula XIII can be prepared via the activation ofthe carboxyIic acid in compounds of formula lq using an appropriatecarboxyIic acid activating agent in an appropriate solvent. Exemplaryactivating agents include carbonyldiimidazole or dicyclohexylcarbodiimide and pentafluorophenol.

[0071] Compounds of formula lq wherein R₃ is —(CH₂)_(z)CO₂H can beprepared with the methods described in Schemes III and IV.

[0072] Compounds of formula Ir wherein R₃ is —(CH₂) SO₂NR₁₀R₁₁ can beprepared via the aminolysis of a sulfonyl chloride of formula XIV usingan amine of the formula NHR₁₀R₁₁ in an inert solvent (e.g., ethers ormethylene chloride).

[0073] Compounds of formula XIV can be prepared by reacting compounds offormula Is with an appropriate dehydrating/chlorinating agent typicallyunder elevated temperatures.

[0074] Compounds of formula Is wherein R₃ is —(CH₂),SO₂OH can beprepared by oxidation of compounds of formula It.

[0075] Compounds of formula It wherein R₃ is —(CH₂)_(z)SH can beprepared by the methods described above in Scheme IV.

[0076] Compounds of formula Iu wherein R₃ is —(CH₂)_(z)NR₁₀(C═O)OR₁₁ canbe prepared by reacting compounds of formula Iv with a chloroformate inan inert solvent.

[0077] Compounds of formula Iw wherein R₃ is —(CH₂)_(z)NR₁₀(C═O)NR₁₁R₁₂can be prepared by reacting compounds of formula Ix with an alkylatingagent under basic conditions in an inert solvent.

[0078] Compounds of formula Ix wherein R₃ is —(CH₂)_(z)NR₁₀(C═O)NHR₁₁,can be prepared by reacting compounds of formula Iv with an isocynate inan inert solvent.

[0079] Compounds of formula Iv can be prepared with the methodsdescribed above in Scheme IV.

[0080] Compounds of formula Iy wherein R₃ and R₅ form a heterocyclocarboxamide ring can be prepared from compounds of formula Iz byhydrolysis and decarboxylation.

[0081] Compounds of formula lz wherein R₃ and R₅ form a 2-carboxylateheterocyclo carboxamide ring can be prepared from compounds of formulaIaa by a base effected cycIization.

[0082] Compounds of formula Iaa wherein R₃ is —CH₂CH(CO₂R₉)₂ and R₅ ishydrogen can be prepared with the methods described in Scheme III.

[0083] Compounds of formula Iab wherein R₃ is —(CH₂)_(z)OR₉(OR₁₀)NR₁₁R₁₂can be prepared from compounds of formula Iac by a base-effectedalkylation.

[0084] Compounds of formula Iac wherein R₃ is —(CH₂)_(z)OR₉(OH) NR₁₁R₁₂can be prepared from compounds of formula Iab by an aminolysis of theepoxide.

[0085] Compounds of formula Iad wherein R₃ is —(CH₂)_(z)OR₉NR₁₀R₁₁ canbe prepared by the method described in Scheme IV.

[0086] Compounds of formula Ia wherein R₃ is hydrogen can also beprepared from compounds of formula XV by a base-effected alkylation.

[0087] Compounds of formula XV can be prepared from compounds of formulaXVI by a Curtius rearrangement.

[0088] Compounds of formula XVI can be prepared by reacting compounds offormula XVII with an appropriate methyl ketone.

[0089] Compounds of formula XVII are either commercially available oravailable via methods known to one skilled in the art.

PREFERRED COMPOUNDS

[0090] Preferred compounds of this invention are those of formula (I)and/or pharmaceutically acceptable salts thereof having the followingdefinitions:

[0091] wherein,

[0092] R₂, R₆, and R₇ are independently hydrogen, halogen, alkyl,substituted alkyl, nitro, cyano, aryl, or heteroaryl;

[0093] R₈ is hydrogen, alkyl, or substituted alkyl, including —(CH₂)_(n)NR₁₃,R₁₄, wherein R₁₃ and R₁₄ (i) are independently selected fromhydrogen, alkyl, or substituted alkyl, or (ii) taken together form aheterocylco ring;

[0094] R₃ is —(CH₂)_(z)Y;

[0095] R₄ is hydrogen, lower alkyl, or forms a heterocyclo ring with Yor R₃;

[0096] R₅ is substituted alkyl;

[0097] R6 is hydrogen, halogen, trifluoromethyl, nitro, cyano, or aryl;

[0098] Y is (i) independently selected from —OR₉, —CO₂R₉, —CH (CO₂R₉)₂,—O(C═O) NR₁₀R₁₁, —NR₁₀R₁₁, —NR₁₀(C═O)NR ₁₁R₁₂,—CH[(C═O)NR₁₀R₁₁]₂,₂,—(C═O)NR₁₀R₁₁,—NR₁₀(C═O)R₁₂, —S(O)_(m)R₉,—SO₂NR₁₀R₁₁ l, imidazole, substituted imidazole, triazole, substitutedtriazole, or cyano, or (ii) taken together with R₄ or R₅, forming aheterocylo ring therewith;

[0099] m is 0, 1, or 2;

[0100] n is 0, 1, 2, or 3;

[0101] z is 0, 1, 2, or 3;

[0102] R₉ is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy,cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, orpentafluorophenyl; and R₁₀, R₁₁, and R₁₂ (i) are independently selectedfrom hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, heterocyclo, or heteroaryl; or (ii) taken togetherwherein R₁₀ with R₁₁ or R₁₂forms a three-to seven-membered heterocycloring, or R₁₀ with R₁₂ forms a three-to seven-membered heterocyclo ring.

[0103] More preferred are the compounds of formula (I), above, and/orpharmaceutically acceptable salts thereof, wherein

[0104] R₂ is hydrogen, halogen, lower alkyl, or pyridine;

[0105] R₃ is —(CH₂)_(z)Y;

[0106] R₄ is hydrogen, methyl, or forms a heterocyclo ring with Y or R₃;

[0107] R₅ is substituted alkyl, wherein said substituted alkyl comprisesan aryl, cycloalkyl, or heteroaryl substituent;

[0108] R₆ is hydrogen, halogen, trifluoromethyl, or cyano;

[0109] R₇ is hydrogen or trifluoromethyl;

[0110] R₈ is hydrogen, alkyl, substituted alkyl, or—(CH₂)nNR₁₃, R₁₄,wherein R₁₃and R₁₄ (i) are independently selected from hydrogen, alkyl,or substituted alkyl, or (ii) together form a heterocylco ring;

[0111] Y is (i) —OR₉, —CO₂R₉, —CH(CO₂R₉)₂,—OR₉NR ₁₀R₁₁ —NR₁₀R₁₁,—(C═O)NR₁₀R₁₁,—NR₁₀(C═O)R₁₂ or (ii) together with R₄forms a heterocyloring;

[0112] n is 0, 1, 2, or3;

[0113] z is 0, 1, 2, or 3;

[0114] R₉ is hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, orpentafluorophenyl;

[0115] R₁₀ and R₁₁ are (i) independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl,heterocyclo, or heteroaryl; or (ii) taken together wherein R₁₀ andR₁₁,forms a three-to seven-membered heterocyclo ring; and R₁₂ is aryl,cycloalkyl, or heteroaryl.

[0116] Advantageously, R₅comprises cycloalkyl or an alkyl substitutedwith aryl. When R₅ is an alkyl substituted with an aryl, advantageouslythe aryl has one to two substituents wherein at least one of thesubstituents is selected from halogen (e.g., chloro, bromo, fluoro),alkoxy (e.g., methoxy), or a lower alkyl. Advantageously, when Rgcomprises a heterocyclo ring with a nitrogen heteroatom, said nitrogenheteroatom has a substituent X, selected from lower alkyl, substitutedalkyl, and cycloalkyl When R₄ and R₃ (or Y) form a heterocyclo ring,said ring advantageously is unsubstituted or has at least onesubstituent X₂ comprising CO₂(alkyl).

[0117] Most preferred are the compounds of formula (I) and/orpharmaceutically acceptable salts thereof, wherein:

[0118] R₂ is hydrogen or chloro;

[0119] R₃ is —(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3;

[0120] R₄ is hydrogen;

[0121] R₅ is 3-chloro-4-methoxyphenylmethyl;

[0122] R6 is cyano;

[0123] R₇ is hydrogen;

[0124] R₈ is hydrogen, alkyl, or substituted alkyl;

[0125] Y is —OR₉,—NR₁₀R₁₁ —CO₂R₉, or —(C═O)NR₁₀R₁₁; R₉ is hydrogen,alkyl, or substituted alkyl; and R₁₀ and R₁₁ (i) are each independentlyhydrogen, alkyl, substituted alkyl, aryl, heterocyclo, or heteroaryl; or(ii) together form a five-to seven-membered heterocyclo ring.

PREFERRED PHARMACEUTICAL COMPOSITION FOR TREATING cGMP-ASSOCIATEDCONDITIONS

[0126] Preferred pharmaceutical compositions of this invention are thosecompositions adapted for use in treating cGMP-associated conditionscomprising a pharmaceutically acceptable diluent or carrier and at leastone compound of the formula (I) and/or pharmaceutically acceptable saltsthereof:

[0127] wherein, R₂, R₆, and R₇ are independently hydrogen, halogen,alkyl, substituted alkyl, nitro, cyano, aryl, or heteroaryl; R₈ ishydrogen, alkyl, substituted alkyl, or —(CH₂)_(n)NR₁₃,R₁₄, whereinR₁₃and R₁₄ (i) are independently selected from hydrogen, alkyl, orsubstituted alkyl, or (ii) taken together form a heterocylco ring;

[0128] R₃ is hydrogen or —(CH₂)_(z)Y;

[0129] R₄ is hydrogen, lower alkyl, or forms a heterocyclo ring with Yor R₃;

[0130] R₅ is substituted alkyl;

[0131] R₆ is hydrogen, halogen, trifluoromethyl, nitro, cyano or aryl;

[0132] Y is selected (i) independently from —OR₉, —CO₂R₉, —CH (CO₂R₉)₂,—O(C═O) NR₁₀R₁₁, —NR₁₀R₁₁,—NR₁₀(C═O)NR₁₁R₁₂, —CH[(C═O)NR₁₀R₁₁]₂,—(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₁₂ —S(O)_(m)R₉, —SO₂NR₁₀R ₁₁, imidazole,substituted imidazole, triazole, substituted triazole, or cyano, or (ii)together with R₄ or R₅, forming a heterocylo ring therewith;

[0133] m is 0, 1, or 2;

[0134] n is0, 1, 2, or3;

[0135] z is 0, 1, 2, or 3; R₉ is hydrogen, alkyl, substituted alkyl,hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl,heteroaryl, or pentafluorophenyl; and R₁₀, R₁₁, and R₁₂ (i) areindependently selected from hydrogen, alkyl, substituted alkyl, alkoxy,cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, or heteroaryl; or(ii) taken together wherein R₁₀ with R₁₁ or R₁₂forms a three-toseven-membered heterocyclo ring, or R₁₀ with R12 forms a three-toseven-membered heterocyclo ring.

[0136] In the pharmaceutical compositions wherein R₃ of formula (I) ishydrogen, it is preferred that R₆ is cyano. In an alternative embodimentwhere R₃ is hydrogen, R₂ advantageously is selected from heteroarylincluding pyridine. Advantageously, when R₃is hydrogen, R₂does notinclude hydrogen, chlorine, or methyl.

[0137] More preferred pharmaceutical compositions are those including apharmaceutically acceptable diluent or carrier and at least one compoundof the formula (I) and/or pharmaceutically acceptable salts thereof,wherein

[0138] R₂ is hydrogen, halogen, lower alkyl, or pyridine;

[0139] R₃ is hydrogen or —(CH₂)_(z)Y;

[0140] R₄ is hydrogen, methyl, or forms a heterocyclo ring with Y or R₃;

[0141] R₅ is alkyl substituted with aryl, cycloalkyl, or heterocyclo;

[0142] R₆ is hydrogen, halogen, trifluoromethyl, or cyano;

[0143] R₇ is hydrogen or trifluoromethyl;

[0144] R₈ is hydrogen, alkyl, substituted alkyl, or —(CH₂)_(n)NR₁₃,R₁₄,wherein R₁₃ and R₁₄ (i) are independently selected from hydrogen, alkyl,or substituted alkyl, (ii) together form a heterocylco ring;

[0145] Y is (i) —OR₉, —CO₂R₉, —CH(CO₂R₉)₂,—OR₉NR₁₀R₁₁ —NR₁₀R₁₁,—(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₁₂ or (ii) together with R₄forms a heterocyloring;

[0146] n is 0, 1, 2, or 3;

[0147] z is 0, 1, 2, or 3;

[0148] R₉ is hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, orpentafluorophenyl;

[0149] R₁₀ and R₁₁ are (i) independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl,heterocyclo, or heteroaryl; or (ii) taken together wherein R₁₀ and R₁₁,forms a three-to seven-membered heterocyclo ring; and R₁₂ is aryl,cycloalkyl, or heteroaryl.

[0150] Advantageously, R₅ comprises an alkyl substituted with cycloalkylor an aryl group. When R₅ is alkyl substituted with aryl, advantageouslythe aryl has one to two substituents wherein at least one of thesubstituents is selected from halogen (e.g., chloro, bromo, fluoro),alkoxy (e.g., methoxy), or a lower alkyl. Advantageously, when Rgcomprises a heterocyclo ring with a nitrogen heteroatom, said nitrogenheteroatom has a substituent X₁ selected from lower alkyl, substitutedalkyl, and cycloalkyl When R₄ and R₃ (or Y) form a heterocyclo ring,said ring advantageously is unsubstituted or has at least onesubstituent X₂ comprising CO₂(alkyl).

[0151] Most preferred pharmaceutical compositions are those including apharmaceutically acceptable diluent or carrier and at least one compoundof the formula (I) and/or pharmaceutically acceptable salts thereof,wherein

[0152] R₂ is hydrogen or chloro;

[0153] R₃ is —(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3;

[0154] R₄ is hydrogen;

[0155] R₅ is 3-chloro-4-methoxyphenylmethyl;

[0156] R₆ is cyano;

[0157] R₇ is hydrogen;

[0158] R₈ is hydrogen, alkyl or substituted alkyl;

[0159] Y is —OR₉,—NR₁₀R₁₁, —CO₂R₉, —(C═O) NR₁₀R₁₁; R₉ is hydrogen,alkyl, or substituted alkyl; and R₁₀ and R₁₁ (i) are each independentlyhydrogen, alkyl, substituted alkyl, aryl, heterocyclo, or heteroaryl; or(ii) together form a five-to seven-membered heterocyclo ring.

[0160] UtiIity

[0161] The compounds and compositions of this invention inhibit cGMPPDE, and in particular are potent and selective inhibitors of cGMP PDE5. Thus, these compounds and compositions are useful in treatingcGMP-associated conditions. A“cGMP-associated condition”, as usedherein, denotes a disorder which can be treated by inhibiting cGMP PDEor elevating the level of cGMP in a subject, wherein treatment comprisesprevention, partial alleviation, or cure of the disorder. Inhibition ofcGMP PDE or elevation of the cGMP level may occur locally, for example,within certain tissues of the subject, or more extensively throughoutthe subject being treated for such a disorder. Treatment may befaciIitated wherein elevation of the cGMP level potentiates additionalbeneficial therapeutic effects, such as where elevation of the cGMPlevel potentiates the effects of endotheIium-derived relaxing factor.

[0162] The inventive compounds and compositions are useful for treatinga variety of cardiovascular diseases including, but not Iimited to,hypertension, angina (stable, unstable, and variant), (congestive) heartfailure, restenosis, atherosclerosis, and dyslipidemia, as well asreduced blood vessel patency, thrombus, both venous and arterial,myocardial infarction, peripheral vascular disease, stroke, bronchitis,chronic asthma, allergic asthma, allergic rhinitis, glaucoma, benignprostate hyperplasia (BPH),and forms of cancer responsive to theinhibition of cGMP PDE. In addition, these compounds are useful intreating sexual dysfunction in both men (erectile dysfunction, forexample, due to diabetes melIitus, spinal cord injury, radicalprostatectomy, psychogenic etiology or any other cause) and women byimproving blood flow to the genitalia, especially, the corpuscavernosum. The compounds and compositions of this invention also areuseful in treating diabetes melIitus and related conditions, anddiseases of the gastrointestinal tract, such as those characterized bydisorders of gut motility, including gastric paresis.

[0163] The present invention thus provides methods for treatingcGMP-associated conditions, comprising administering to a subject inneed thereof an effective amount of at least one compound of the formulaI or a salt thereof, and/or pharmaceutical compositions as describedabove. Other therapeutic agents such as those described below may beemployed in combination with the compounds of formula I. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compound(s) and compositions.

[0164] The present invention also provides pharmaceutical compositionscapable of treating a cGMP-associated condition, as described above. Thecompositions of the present invention may contain other therapeuticagents as described below, and may be formulated, for example, byemploying conventional solid or Iiquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabiIizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

[0165] The compounds and compositions of formula I may be administeredby any suitable means, for example, orally, such as in the form oftablets, capsules, granules or powders; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular orintrasternal injection or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasallysuch as by inhalation spray; topically, such as in the form of a creamor ointment; rectally such as in the form of suppositories; orliposomally; in dosage unit formulations containing non-toxic,pharmaceutically acceptable vehicles or diluents. These compounds may,for example, be administered in a form suitable for immediate release orextended release. Immediate release or extended release may be achievedby the use of suitable pharmaceutical compositions or, particularly inthe case of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps.

[0166] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalIine cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The compounds of formula Imay also be deIivered through the oral cavity by sublingual and/orbuccal administration. Molded tablets, compressed tablets orfreeze-dried tablets are exemplary forms that may be used. Exemplarycompositions include those formulating the inventive compound(s) withfast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG). Such formulations may also include an excipient to aid mucosaladhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleicanhydride copolymer (e.g., GANTREZ®), and agents to control release suchas polyacryIic copolymer (e.g., CARBOPOL 9340). Lubricants, gIidants,flavors, coloring agents and stabiIizers may also be added for ease offabrication and use.

[0167] Exemplary compositions for nasal aerosol or inhalationadministration include solutions in saIine which may contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance absorption and/or bioavailability, and/or othersolubilizing or dispersing agents such as those known in the art.

[0168] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0169] Exemplary compositions for rectal administration includesuppositories which may contain, for example, suitable non-irritatingexcipients, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures butliquefy and/or dissolve in the rectal cavity to release the drug.

[0170] Exemplary compositions for topical administration include atopical carrier such as PLASTIBASE® (mineral oil gelled withpolyethylene).

[0171] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art, and includesexemplary dosage amounts for an adult human of from about 0.05 to 100mg/kg of body weight of active compound per day, which may beadministered in a single dose or in the form of individual divideddoses, such as from 1 to 4 times per day. It will be understood that thespecific dose level and frequency of dosage for any particular subjectmay be varied and will depend upon a variety of factors, including theactivity of the specific compound employed, the metaboIic stabiIity andlength of action of that compound, the species, age, body weight,general health, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition. Preferred subjects for treatment include animals,most preferably mammalian species such as humans, and domestic animalssuch as dogs, cats, horses, and the Iike, subject to cGMP-associatedconditions.

[0172] The inventive compounds and compositions may be employed alone orin combination with each other and/or other suitable therapeutic agentsuseful in treating cGMP-associated conditions such as other cGMP PDEinhibitors, particularly other cGMP PDE 5 inhibitors, modulators of thelarge-conductance calcium-activated potassium (BK) channels,prostanoids, α-adrenergic agonists, endotheIin antagonists, angiotensinII (especially, subtype AT₁) antagonists, angiotensin converting enzyme(ACE) inhibitors, renin inhibitors, and serotonin (5-HT_(2c)) agonists.

[0173] Exemplary of such other therapeutic agents are the following:phentolamine, yohimbine, papaverine, apomorphine, sildenafil,pyrazolopyrimidinones as described in U.S. Pat. Nos. 5,272,147;5,250,534; 5,426,107; and 5,346,901, quinazolinones as described in U.S.Pat. No. 5,482,941; AT, antagonists such as from losartan, irbesartan,valsartan, and candesartan; ETA antagonists such as bosentan, ABT-627,and those described in U.S. Pat. No. 5,612,359 and U.S. patentapplication Ser. No. 60/035,832, filed Jan. 30, 1997; PDE 5 inhibitorsselected from imidazoquinazoIines (see WO 98/08848), carbazoles (see WO97/03675, WO 97/03985 and WO 95/19978), imidazopurinones (see WO97/19947), benzimidazoles (see WO 97/24334), pyrazoloquinolines (seeU.S. Pat. No. 5,488,055), quinazoIinones as described in U.S. Pat. No.6,087,368, pyridines as described in U.S. patent appIication Ser. No.60/100,655 filed Sep. 16, 1998, anthraniIic acid derivatives (see WO95/18097), fused heterocycles (see WO 98/07430) and thienopyrimidines(see DE 19632423); and 5-HT_(2c). agonists selected from indoles (see J.Med. Chem., 40, 2762-2769 [1997], EP 655440 and EP 657426), andmodulators of the large-conductance calcium-activated potassium (BK)channels as described in U.S. Pat. Nos. 5,565,483 and 5,602,169, and inWO 98/04135 and W098/23273.

[0174] The above other therapeutic agents, when employed in combinationwith the compounds of the present invention, may be used, for example,in those amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. a Thefollowing assay can be employed in ascertaining the degree of activityof a compound as a cGMP PDE inhibitor. Compounds described in thefollowing Examples have been tested in this assay, and have shownactivity.

[0175] PDE Scintillation Proximity Assay Protocol

[0176] Sonicated human platelet homogenates are prepared by the methodof Seiler, et al. (Seiler, S., Gillespie, E., Arnold, A. J., Brassard,C. L., Meanwell, N. A. and Fleming, J. S.,“Imidazoquinoline Derivatives:Potent Inhibitors of Platelet Camp Phosphodiesterase which Elevate CampLevels and Activate Protein Kinase in Platelets,” Thrombosis Research,62: 31-42 (1991)). PDE 5 is abundant in human platelets, and accountsfor approximately 90% of the cGMP hydrolytic activity in thehomogenates. When necessary, PDE 5 can be resolved from other PDEactivities in the homogenates by anion exchange chromatography on a fastprotein liquid chromatography system (FPLC) using a Mono-Q anionexchange column (Pharmacia) eluted with a linear gradient of 10 mM -450mM NaCl.

[0177] The phosphodiesterase activity is assayed using a commerciallyavailable phosphodiesterase [³H]cGMP scintillation proximity (SPA) assaykit (Amersham). The manufacturer's protocol is followed explicitlyexcept that the reactions are carried out at RT and 3 mM nonradioactivecGMP is included in the suspension of SPA beads to prevent the synthesisof any additional radioactive products.

[0178] All documents cited in the present specification are incorporatedherein by reference in their entirety.

[0179] The following Examples illustrate embodiments of the inventivecompounds and starting materials, and are not intended to limit thescope of the claims. For ease of reference, the following abbreviationsare used in the Examples, below:

[0180] Abbreviations

[0181] DMSO=dimethylsulfoxide

[0182] HPLC=high pressure Iiquid chromatography

[0183] LRMS=low resolution mass spectrometry

[0184] mp=melting point

[0185] tic =thin layer chromatography

[0186] RT =room temperature

[0187] h =hour(s)

[0188] Ac =acetyl

[0189] Et =ethyl

[0190] Me =methyl

[0191] HOAc =acetate

[0192] EtOAc =ethyl acetate

[0193] EDAC •HCl =ethyl-3-(dimethylamino)propyl carbodiimide,

[0194] hydrochloride salt

[0195] HOBT =hydroxybenztriazole

[0196] NMP =N-methyl pyrrolidinone

[0197] TEA =triethylamine

PREPARATION OF STARTING MATERIALS Preparation 1 2-Amino-5-bromo-benyzlalcohol

[0198]

[0199] To 13 mmol of methyl 2-amino-5-bromobenzoate in 20 mL of THF atRT was added 65 mmol of 1M lithium tri-tert-butoxyaluminohydride over10-15 minutes. The solution was heated at reflux for 17 hours. Thesolution was cooled, poured directly onto siIica gel, and eluted withmethylene chloride/ethyl acetate; 3:1 followed by 1:1. The product waseluted with 100% methanol to give 2.59 g of the title compound as anoff-white solid. MH⁺: 202; LC: 1.09′.

Preparation 2 Diethyl 2-(4-cyanophenylamino)methylenemalonate

[0200]

[0201] To 5.00 g (42.3 mmol) 4-aminobenzonitrile (Aldrich, 98%) wasadded 10.1 g (9.41 mL, 46.6 mmol, 1.1 eq) diethylethoxymethylenemalonate(Aldrich, 99%), and the mixture was dissolved in 50 mL toluene (HPLCgrade). The solution was refluxed for four hours with a condensor opento the air. The solution was then poured into 200 mL hexane, and theresulting white precipitate was filtered and washed well with morehexane to yield 10.62 g (37.0 mmol, 85% yield) of the title compound asa slightly off-white solid (per LC/MS and ₁H NMR). LC [MH₊] 289, 97%purity.

Preparations 3-6 Diethyl 2-(arylamino)methylenemalonate

[0202]

[0203] Preparations 3-6 of formula (P1) having values for R₆, R₈ listedin Table 1 were prepared b y the same method as in preparation 2, usingthe corresponding 4 amino-benzene. TABLE 1 Preparation R₆ R₈ 3 Et CN 4Cl CN 5 HOCH₂ Br 6 CO₂CH₃ Br

Preparation 7 Diethyl2-(2-acetoxymethyl-4-bromophenylamino)methylenemalonate

[0204]

[0205] To a solution of 5.83 mmole of product from preparation 5 in 5mlof pyridine was added 8.74 mmole of acetic anhydride over 15 minutes andthe mixture stirred at RT for 1.5 hours. Another 8.74 mmole of aceticanhydride were added, and the mixture stirred at RT for 15.5 hours.Another 2.94 mmole of acetic anhydride were added and the mixturestirred at RT for 4 hours. The mixture was poured into water, and anorganic layer extracted with ethyl acetate. The organic layer was washedwith water and saturated NaCl, dried over MgSO₄, and filtered. Thefiltrate was concentrated to give 2.10 g of the title compound as anoff-white solid. MH₊: 416; LC: 4.25′.

Preparation 8 6-Cyano-4-hydroxyguinoline-3-carboxyIic acid ethyl ester

[0206]

[0207] To 100 mL vigorously refluxing diphenyl ether (Aldrich) was addedin open air, in portions over the course of one hour, 10.5 g (36.5 mmol)diethyl 2-(4-cyanophenylamino)methylenemalonate. The solution wasrefluxed for one additional hour. After allowing the solution to cool tobelow 100° C., it was poured into 200 mL hexane. The resultingprecipitate was filtered and washed well with hexane to yield 8.39 g(34.6 mmol, 94%) of the title compound as a Iight brown solid: MH₊:243,mp>265° C.

Preparations 9-12 6,8-Disubstituted 4-hydroxyguinoline-3-carboxylic acidethyl esters

[0208]

[0209] Preparations 9-12 of formula (P2) wherein R₆ and R₈ have thevalues Iisted in Table 2, were prepared by the same method as inpreparation 8, using an appropriately substituted diethyl2-(phenylamino) methylenemalonate. TABLE 2 Preparation R₆ R₈  9 CN Et 10CN Cl 11 Br AcOCH₂— 12 Br —CO₂CH₃

Preparation 13 4-Chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester

[0210]

[0211] To 9.50 g (39.2 mmol) ethyl6-cyano-4-hydroxyquinoline-3-carboxylic acid was added 50 mL POCl₃(Aldrich, 99%), and the resulting mixture was refluxed for 48 hrs. ThePOCl₃ was evaporated under reduced pressure, and the residue codistilledonce with CHCl₃, and twice with toluene. The resulting brown solid wasdissolved in CH₂Cl₃and treated with triethylamine until aqueous washingsof aliquots had pH>10. The solution was then filtered through a 2″silica pad to yield 10.5 g (40.2 mmol, 103% yield) of the title compoundas an off-white crystalIine solid; MH₊: 261, 97% purity.

Preparations 14-22 4-Chloroquinoline-3-carboxylic acid ethyl esters

[0212]

[0213] The compounds of formula (P3) were prepared, wherein R₂, R₆, R₇,and R₈ have the values Iisted in Table 3, using the same method as inpreparation 13, with an appropriately-substituted ethyl4-hydroxyquinoline-3-carboxylic acid. TABLE 3 Preparation R₂ R₆ R₇ R₈ 14H CN H Et 15 H CN H Cl 16 H H CF₃ H 17 H CF₃ H H 18 H Br H AcOCH₂ 19 HBr H CO₂CH₃ 20 Cl Br H H 21 Cl CN H H 22 Cl CN H Et

Preparations 23 a) and b) a) Methyl 2-amino-5-cyanobenzoate b) Methyl2-amino-3-ethyl-5-cyanobenzoate

[0214]

[0215] A mixture of methyl 2-amino-5-bromobenzoate (4.6 g, 20 mmol), andCuCN (1.97 g, 22 mmol) in NMP (20 mL) was heated to 190° C. and 3 h. Thereaction mixture was poured into a solution of ethylene diamine 4 mL) inH₂O(16 mL) and extracted with toluene (4×20 mL). The extracts were dried(Na₂SO₄). Removal of the solvent gave the title compound a) (i.e., R₈ ishydrogen). Use of methyl 2-amino-5-bromo-3-ethyl bromobenzoate gave thetitle compound b) (iLe., R₈ is ethyl).

Preparations 24 a) and b) a)6-Bromo-2,4-dihydroxylquinoline-3-carboxylic acid ethyl ester b)6-Cyano-2,4-dihydroxylquinoline-3-carboxylic acid ethyl ester

[0216]

[0217] wherein R₆ is Br or CN.

[0218] Diethyl malonate was added to a freshly prepared solution ofsodium ethoxide in ethyl alcohol. The resulting mixture was stirred for30 min. To it was then added dropwise a solution of2-amino-5-bromobenzoic acid methyl ester in ethyl alcohol. The resultantmixture was refluxed overnight. The ethyl alcohol was removed underreduced pressure, and the residue was dissolved in water and extractedwith EtOAc. The aqueous layer was acidified with glacial AcOH to pH5.The precipitate was collected by filtration to yield 2.6 g, (94% yield)the title compound a) (wherein R₆ is Br). Use of 1.76 g (10 mmol)2-amino-5-cyanobenzoic acid methyl ester yielded 1.7 g (66% yield) ofthe title compound b) (wherein R₆ is CN).

Preparation 25 6-Cyano-2,4-dihydroxyl-8-ethylquinoline-3-carboxylic acidethyl ester

[0219]

[0220] To a solution of methyl 2-amino-5-cyano-3-ethylbenzoate (1.36 g,6.2 mmol) and TEA (2.6 mL, 18.6 mmol) in THF (50 mL) was added methylmalonyl chloride (1 mL, 9.3 mmol). The mixture was stirred at RT forovernight. Additional TEA (2.6 mL) and methyl malonyl chloride (1 mL)were added, and the reaction was continued for another 24 h. The mixturewas diluted with EtOAc and washed with H₂O and brine. The solvent wasremoved, and the residue was chromatographed (silica gel, EtOAc/hexane,3:7) to give the amide intermediate. NaH (400 mg, 60% oil dispersion)was washed with dry hexane and dried under nitrogen. To it was added asolution of methyl 2-amino-5-cyano-3-ethylbenzoate (1 g, 3 mmol) intoluene (40 mL), which was followed by dropwise addition of EtOH (4 mL).The resultant mixture was refluxed for overnight. The solvent wasremoved and the residue was dissolved in H₂O (insoluable particulateswere removed by filtration). Upon acidification with HOAc, the titlecompound (590 mg) was precipitated out and collected by filtration.

Preparation 26 6-Bromo-2-(2-pyridinyl)quinoline-4-carboxylic acid

[0221]

[0222] To a suspension of 5-bromo isatin (5 g, 20.5 mmol) and2-acetylpyridine (2.5 g, 20.5 mmol) in aqueous KOH (1.2 g, 33%) wasadded EtOH until a solution formed. The mixture was refluxed over night.The reaction mixture was neutralized with HOAc (50%) and filtered. Thesolid was resuspended in EtOH and filtered to give the title compound(5.5 g). LC: 1.66 and MH₊: 329.

Preparation 27 Azido-6-bromo-2-(2-pyridinyl)quinoline-4-carboxylate

[0223]

[0224] A mixture of 6-bromo-2-(2-pyridine)quinoline-3-carboxylic acid(2.5 g) in SOCl₂ (30 mL) was refluxed for 2 h, and the excess SOCl₂ wasremoved. The residue was resuspended in acetone (100 mL). To thesuspension was added a solution of NaN₃ (0.5 g) in water (50 mL) andstirred for 2h. The solid product was collected by filtration and washedthroughly with water, then dried at 40° C. overnight to give the titlecompound (2.3 g). LC: 2.13′.

Preparation 28 6-Bromo-4-tbutoxycarbonylamino-2-(2-pyridinyl)quinoline

[0225]

[0226] A mixture of preparation 27 (2 g) in toluene (50 mL) was refluxedfor 20 3 h. Then tBuOH (1 mL) was added and continue to reflux for 2 h,The reaction mixture was cooled to RT and filtered. The filtrate wasconcentrated to give the title compound (2 g).

Example 14-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyanoquinoline-3-carboxylicacid ethyl ester

[0227]

[0228] To 10.0 g (38.4 mmol) 4-chloro-6-cyanoquinoline-3-carboxylic acidethyl ester was added 10.4 g (50 mmol, 1.5 eq) 3-chloro-4-methoxybenzylamine hydrochloride and 35 mL (228 mmol, 6 eq) diisopropylethylamine(Aldrich, 99.5+%). The mixture was dispersed in 200 mL n-propanol andbrought to reflux for two hours. The solution was then poured into 500mL water. The resulting precipitate was filtered, then washed with 500mL water, then twice washed with 50 mL absolute ethanol to yield 14.87 g(37.6 mmol, 97% yield) of the title compound as a white fiberous solidafter codistilIing with absolute ethanol: mp: 161-162° C.; LC/MS (M/Z)396 [M+H] observed, 97% purity.

Examples 2-55 4-Aminoquinoline-3-carboxylic acid ethyl esters

[0229]

[0230] Using the same or similar method of Example 1, compounds havingthe formula (lae) were prepared, wherein R₂, R₅, R₆, R₇, and R₈ have thevalues listed in Table 4, starting with corresponding3-carboxylate-4-uinolines and amine hydrochlorides. TABLE 4 HPLC Ex.retention No. —R₅ R₂ R₆ R₇ R₈ time (min.) MH⁺ 2

H H CF₃ H 3.63 439 3

Cl Br H H 4.75 437 4

Cl Br H H 4.56 485 5

H CF₃ H H 3.64 439 6

H CN H H 3.73 352 7

H CN H H 3.82 352 8

H F H H 3.41 389 9

H Br H CO₂nPr 3.29 535 10

H Br H CO₂Me 3.52 507 11

H Br H H 2.82 449 12

H CN H Et 2.78 424 13

H CN H Cl 3.89^(b) 430 14

H Br H AcOCH₂ 1.73^(a) 521 15

H Br H Me 3.68 463 16

H CN H Et 1.56^(a) 394 17

H CN H Et l.68^(a) 428 18

H CN H Et 1.65^(a) 428 19

H CN H Et 1.46^(a) 390 20

H CN H Et 1.73^(a) 380 21

H CN H Et 1.73^(a) 380 22

H CN H CO₂nPr 3.43 482 23

H CN H CO₂Me 3.11 454 24

H CN H CO₂Et 3.27 468 25

H CN H Et 1.23^(a) 350 26

H CN H Et 1.33^(a) 404 27

H CN H Et 1.49^(a) 428 28

H CN H Et 1.38^(a) 396 29

H CN H Et 1.49^(a) 428 30

H CN H Et 1.65^(a) 402 31

H CN H Et 1.70^(a) 416 32

H CN H Et 1.60^(a) 428 33

H CN H Et 1.42^(a) 420 34

H CN H Et 1.39^(a) 420 35

H CN H Et 1.53^(a) 444 36

H CN H Et 1.53^(a) 442 37

H CN H Et 1.28^(a) 550 38

H CN H Et 1.55^(a) 446 39

H CN H Et 1.34^(a) 444 40

H CN H Et 3.54 374 41

H CN H Et 3.55 374 42

H CN H Et 3.94 452 43

H CN H Et 3.95 452 44

H CN H Et 3.78 388 45

H CN H Et 3.77 388 46

H CN H Et 3.26 360 47

H CN H Et 3.65 438 48

H CN H Et 3.53 374 49

H CN H Et 1.38^(a) 426 50

H CN H Et 1.46^(a) 406 51

H CN H Et 1.46^(a) 386 52

H CN H Et 1.80^(a) 442 53

H CN H Et 1.41^(a) 434 54

H CN H Et 1.36^(a) 448 55

H CN H Et 1.52^(a) 424

Example 56 6-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-hydroxymethylquinoline-3-carboxylic acid ethyl ester

[0231]

[0232] A mixture of 1.84 mmole6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-(acetoxymethyl)quinoline-3-carboxylicacid ethyl ester (ie., Example 14) and 1.84 mmole of potassium carbonatein 20 mL of ethanol was stirred at RT for 20 hours. The mixture wasconcentrated, and the residue was diluted with water and extracted withethyl acetate. The resultant organic layer was dried over MgSO₄ andfiltered, and the filtrate concentrated to give 0.85 g of the titlecompound as a tan solid. MS: 481; LC: 3.43′.

Example 57 6-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-(chloromethyl)quinoline-3-carboxylic acid ethyl ester

[0233]

[0234] A solution of 1.73 mmole6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl)amino)-8-hydroxymethylquinoline-3-carboxylicacid ethyl ester (i.e., Example 56) in 8 ml of thionyl chloride wasstirred at RT for 1.5 hours. The solution was concentrated to give 0.86g of the title compound as an orange foam. MS: 499; LC: 4.15′

Example 58 6-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-(N,N-dimethylaminomethyl)quinoline-3-carboxylic acid ethyl ester

[0235]

[0236] A solution of 0.20 mmole of example 57 and 2 mmole of 2Mdimethyamine in 1 ml of THF was stirred at RT for 22 hours. Anadditional 0.25 ml of 2M dimethylamine in THF was added and the solutionstirred for 4 hours. The solution was diluted with ethyl acetate andwashed with water. The organic layer was dried over MgSO₄ and filtered,and the filtrate was concentrated. The residue was chromatographed onsilica gel eluted with methylene chloride followed by methylenechloride/ethyl acetate; 95:5 and finally with ethyl acetate to give 71mg of the title compound as a beige solid. MS: 507; LC: 3.71′

Example 594-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid

[0237]

[0238] To 8.0 g (20 mmol) 4-(3-Chloro-4 -methoxyphenylmethylamino)-6-cyanoquinoline-3-carboxylic acid ethyl ester was added 100 mL THF, 100mL MeOH and 100 mL 1M NaOH, and the resulting mixture was stirred well.The solids gradually dissolved as the reaction progressed. After 1 h,the THF and most of the MeOH was evaporated under reduced pressure toleave an aqueous slurry of a white solid. The slurry was acidified to pH1.5 with HCl, stirred well for 1 h, and then filtered and washed wellwith water to give 7.5 g (20 mmol, ˜100% yield) of a white chalky solid.Codistilling twice to dryness with absolute ethanol afforded the titlecompound: LC/MS: M/Z 368 (M+H) observed, 90+% purity; mp: decomposed255-260° C. LC 2.93′.

Examples 60-644-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylic acids

[0239]

[0240] Using the same or similar method as described in Example 59,compounds having the formula (laf) were prepared, wherein R₂, R₆, R₇,and R₈ have the values listed in Table 5, starting with corresponding3-carboxylatequinolines TABLE 5 HPLC Ex. retention No. R₂ R₆ R₇ R₈ time(min.) MH⁺ 60 H H CF₃ H 3.67 411 61 Cl Br H H 4.29 455 62 H F H H 3.31361 63 H CN H Et 2.56 396 64 H CN H Cl 3.23 402

Example 65 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile

[0241]

[0242] To 2.16 g (5.87 mmol) 4-[[(3-chloro-4-methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylic acid wasadded 50 mL diphenyl ether (Aldrich), and nitrogen was vigorouslybubbled through this mixture for 20 minutes. The resulting mixture wasthen heated to 240 ° C. under nitrogen for 30 minutes. During the courseof the reaction, the dispersed starting material slowly dissolved, andgas evolution was observed. The resulting solution was poured into 200mL hexane, and a precipitated solid was filtered to yield 1.43 g (4.42mmol, 75% yield) of the title compound as a off-white solid: LCIMS: M/Z324 (M+H) observed, 96% purity; mp: decomposed 227-230 ° C. LC: 2.84′.

Example 664-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile

[0243]

[0244] The reaction procedure used was similar to that described forExample 65 with the following changes: 101 mg (0.255 mmol) of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid was used to afford 51 mg (57% yield) of the title compound. LC:1.20′ M/Z 352 mp: 206-207 ° C.

Example 674-[[(3-Chloro-4-methoxyphenyl)methyl]N-methylamino]-6-quinolinecarbonitrile

[0245]

[0246] To 250 mg 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile (i.e., Example 65) was added 50 mgof NaH, and the mixture was flushed with nitrogen. 5 mL of DMF wasadded, and it was stirred for half hour. To the mixture was then added70 μL of CH₃I, and it was stirred at RT. After 1 hour the reaction wasquenched with aqueous NH₄Cl and diluted with water, and the precipitatecollected by filtration to give (153 mg) of the title compound. LC:2.48;M/Z 338 m.p. 153-155° C.

Example 684-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyanoquinoline-3-carboxylicacid pentafluorophenyl ester

[0247]

[0248] To 275 mg (0.748 mmol) of4-[[(3-chloro-4-methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylicacid was added 276 mg (1.50 mmol, 2.0 eq) pentafluorophenol, and themixture was dispersed in 5 mL anhydrous DMF under nitrogen. To thisdispersion was added a solution of 231 mg (1.12 mmol, 1.5 eq) ofdicyclohexylcarbodiimide (Aldrich) in 2 mL anhydrous ethyl acetate atRT. The resulting mixture was stirred for 18 hours. The reaction wasthen diluted with 10 mL EtAc, and the white precipitate was filtered anddiscarded. The filtrate was concentrated in vacuo, and the residue wastriturated with 5% MeOH/95% CH ₂Cl₂ to give 164 mg (0.307 mmol, 41%yield) of the title compound as a white solid: LC/MS: M/Z 534 (M+H)observed, 100% purity; mp: decomposed 215-217 ° C. LC: 4.15.

Example 694-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethylquinoline-3-carboxylicacid pentafluorophenyl ester

[0249]

[0250] The reaction procedure used was similar to that described forExample 68 with the following changes: 3.95 g (10.0 mmol)4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid was used to afford 2.81 g (5.00 mmol, 50% yield) of the titlecompound as a white solid: mp: 169-170 ° C.; LC: 2.14^(a.), MH₊562.

Examples 70-1224-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxamides

[0251]

[0252] Compounds having the formula (lag), wherein R₂, R₆, R₇, R₈, R₁₀,andR₁₁ have the values listed in Table 6, were prepared by the followingting with corresponding 3-carboxylatequinolines and an amine:

[0253] To 1 eq of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-boxylicacid pentafluorophenyl ester in THF (approx. 25 mg per 1 mL THF) wasadded 2 eq of an appropriate primary or secondary amine. The resultingreaction solution was allowed to stir for 18 hours at RT. The THF wasthe evaporated in vacuo, and the residue was triturated with a 1:1solution of ether/hexane. The precipitated solid was filtered and washedwith 1:1 ether/hexane to yield the desired4-[[(3-chloro-4-methoxyphenyl) mrthyl]amino]-3-quinolinecarboxamide.Yields were generally >25%. TABLE 6 HPLC Ex. retention No. R₂ R₆ R₇ R₈—NR₁₀R₁₁ time (min.) MH⁺ 70 H H CF₃ H —NH₂ 3.35 410 71 H H CF₃ H

3.09 501 72 H H CF₃ H

3.06 515 73 H H CF₃ H

1.78^(a) 523 74 H H CF₃ H

1.81^(a) 482 75 H H CF₃ H

1.92^(a) 508 76 H H CF₃ H

1.92^(a) 438 77 H H CF₃ H

1.73^(a) 494 78 H CN H H

2.49 458 79 H CN H H

2.56 480 80 H CN H H

2.45 507 81 H CN H H

2.18 450 82 H CN H H —NH₂ 2.73 367 83 H CN H H

2.99 423 84 H CN H H

1.57^(a) 438 85 H CN H H

2.57 410 86 H CN H H

1.47^(a) 503 87 H CN H H

1.91^(a) 478 88 H CN H H

1.55 464 89 H CN H H

1.80 504 90 H CN H H

1.63 494 91 H CN H H

1.64 504 92 H CN H H

1.70 518 93 H CN H Et —NH₂ 2.34 395 94 H CN H Et

2.20 486 95 H CN H Et

2.05 532 96 H CN H Et

1.92 506 97 H CN H H

2.38 478 98 Cl Br H H

3.36 551 99 Cl Br H H

3.38 565 100 Cl Br H H

3.48 591 101 Cl Br H H

3.49 545 102 Cl Br H H

2.74 537 103 Cl Br H H

1.57^(a) 539 104 Cl Br H H

1.52^(a) 594 105 Cl Br H H

1.55^(a) 581 106 Cl Br H H

3.61 579 107 Cl CN H H

3.09 492 108 Cl CN H Et

1.73^(a) 520 109 H CN H Et

1.35^(a) 449 110 H CN H Et

1.21^(a) 532

Examples 111-1794-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamides

[0254]

[0255] Compounds having the formula (lah), wherein R₁₀ and R₁₁, have thevalues listed in Table 7, were prepared by the following method:

[0256] To a solution of 1.0 eq of the appropriate primary amine or 2.0eq of the appropriate secondary amine in anhydrous THF (3 mL) was added15 mg4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid pentafluorophenyl ester (0.028 mmol). Where the amine was ahydrohalide salt, 3 eq of triethylamine were also added. The solutionswere stirred overnight at 50 0° C. then filtered and purified by SCXcartridges (2 g capacity, p-toluene sulfonic acid) on a Bohdan SPD robot(10 mL MeOH wash, 10 mL 2M NH₃/MeOH elution). The desired4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamidewas recovered either by filtration (manual), by concentration of the SCXeluent (by Savant Speedvac), or (if further purification was required)by preparative HPLC (Shimadzu). Average purity: 93% (LC/MS). Averageyield: >25%. TABLE 8 HPLC retention Ex. time No. —NR₁₀R₁₁ (min.)^(a) MH⁺111

1.63 395 112

1.83 423 113

1.96 435 114

2.17 451 115

1.84 439 116

1.70 455 117

1.81 439 118

2.01 467 119

1.97 451 120

1.69 411 121

1.66 425 122

0.64 439 123

1.77 453 124

2.16 453 125

1.78 453 126

1.57 455 127

1.70 465 128

1.78 453 129

1.83 467 130

1.66 452 131

1.77 492 132

1.59 466 133

1.49 466 134

1.49 480 135

1.74 494 136

1.60 464 137

1.66 478 138

1.48 492 139

1.53 424 140

1.53 440 141

1.58 452 142

1.54 452 143

1.58 480 144

1.52 494 145

1.63 506 146

1.59 478 147

1.46 478 148

1.96 522 149

1.73 540 150

1.75 514 151

1.54 466 152

1.63 494 153

1.63 437 154

1.78 453 155

1.66 452 156

1.55 494 157

1.59 437 158

1.59 478 159

1.43 464 160

1.83 435 161

1.59 451 162

1.69 479 163

1.91 507 164

1.63 478 165

1.63 478 166

1.90 493 167

1.43 436 168

1.43 521 169

1.41 480 170

1.64 518 171

1.48 513 172

1.76 514 173

1.45 450 174

1.44 464 175

2.00 457 176

1.61 458 177

1.87 458 178

1.86 487 179

2.25 501

Example 1804-[[(3-CHloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile

[0257]

[0258] To 530 mg (1.0 mmol) of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid pentafluorophenyl ester was added 15 mL of anhydrous DMF, and theresulting mixture was cooled to 0° C. A solution of 75 mg of NaBH ₄ in 5mL of was added to the reaction mixture, resulting in a clear redsolution with gas evolution. After stirring for 1 hour at 0 ° C., thereaction was quenched with 2% TFA/MeOH, and the solvent was removedunder reduced pressure. The oily residue was purified by flashchromatography (silica gel, 3-5% MeOH/CH₂Cl₂) to afford 87 mg (25%yield) of the title compound. LC: 2.60′ ; MH₊: 354.

Example 1814-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile

[0259]

[0260] To a suspension of 100 mg (0.236 mmol) of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethylquinoline-3-carboxylicacid ethyl ester in 2.8 mL anhydrous THF under nitrogen, was added 1.2mL (5.0 eq) of 1M lithium tri-t-butoxyaluminohydride/THF. The resultingmixture was refluxed overnight with stirring. The reaction was quenchedwith 1 mL of MeOH and partitioned between 75 mL 1M NaOH and 100 mLCH₂CI₂. The organic phase was washed with 1M NaOH (2×30 mL) and driedover MgSO₄. Removal of the solvent under reduced pressure gave 75 mg(84% yield) of the title compound as a Iight yellow solid. Theanalytical sample was obtained by trituration in ether: mp: 188-189° C.LC: 3.15′; MH_(+:) 382.

Examples 182-190 4-Amino-3-(hydroxymethyl)quinolines

[0261]

[0262] Using the same method of Example 181, compounds having theformula (lai) were prepared, wherein R₅, R₆, and R₈ have the valueslisted in Table 8 using an appropriate amine (having the group R₅) InExample 190, the reaction was started with3-ethyl-8-methyldicarboxylatequinoline. TABLE 8 HPLC retention Ex. No.—R₅ R₆ R₈ time (min.) MH⁺ Found 182

Br H 2.41 407 183

CN Cl 2.92 388 184

CN Et 1.50^(a) 338 185

CN Et 1.51^(a) 338 186

CN Et 1.45^(a) 386 187

CN Et 1.43^(a) 386 188

CN Et 1.38^(a) 352 189

CN Et 1.25^(a) 348 190

CN —(CH₂)OH 2.59 384

Examples 191-194 3-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

[0263]

[0264] Compounds having the formula (laj) were prepared, wherein R₁₀ andR₁₁ have the values listed in Table 9, by the following method.

[0265] To 70 mg 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile was added 5 mLanhydrous CH₂Cl₂ and 70 μL (0.44 mmol, 2.0 eq) diisopropylethylamine,and the resulting solution was cooled to 0° C. under nitrogen.Methanesulfonyl chloride (17 μL, 0.22 mmol, 1.1 eq) was then added, andthe resulting reaction solution was stirred at 0° C. for 30 minutes. Thesolution was then quenched with 0.24 mmol (1.1 eq) of the appropriateamine (having groups R₁₀, R₁₁), and the resulting solution was stirredfor 30 minutes. The solvent was evaporated under reduced pressure andthe residue was chromatographed in 5% MeOH/CH₂Cl₂ to yield the titlecompound. TABLE 9 HPLC Ex. retention No. —NR₁₀R₁₂ time (min.) MH⁺ 191

2.39 436 192 —NH₂ 1.12 353 193

1.83 444 194

1.84 421

Example 195 6-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(4-methyl-1-piperazinyl)methyl]quinoline

[0266]

[0267] To 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-bromoquinoline was added SOCl₂,and the resultingreaction solution was stirred at RT under nitrogen for 30 minutes. TheSOCl₂ was then evaporated under reduced pressure, and the residue wasleft overnight under high vacuum. The yellow residue was redissolved inanhydrous DMF, and this solution was then added to a solution ofN-methylpiperazine in anhydrous THF. The resulting reaction solution wasstirred for 6 hours at RT, by which time HPLC showed the reaction to becomplete. After evaporating the solvent, the crude product waschromatographed in 3% MeOH/CH₂Cl₂ to yield the title compound. LC:2.12′; MH₊: 489

Examples 196-224 3-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

[0268]

[0269] Compounds having the formula (lak) were prepared, wherein valuesfor R₂, R₈, R₁₀ and R₁₁ are as in Table 10, using the same or similarmethod as in Example 195, starting with the corresponding4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile.TABLE 10 HPLC retention Ex. time MH⁺ No. —NR₁₀R₁₁ R₂ R₈ (min.) Found 196

H H 2.55 437 197

H H 3.43 465 198

Cl H 1.43^(a) 471 199

H H 2.40 381 200

H H 2.43 449 201

H H 1.96 437 202

H H 2.21 435 203

H H 2.24 451 204

H H 1.81 437 205

H H 1.60 423 206

H H 1.97 451 207

H H 2.33 435 208

H H 2.61 435 209

H H 1.86 423 210

H H 2.74 449 211

H H 2.25 451 212

H H 1.17^(a) 437 213

H H 2.80 477 214

H H 2.50 461 215

H H 2.45 473 216

H Et 1.34^(a) 465 217

H H 2.40 443 218

H Et 1.27^(a) 465 219

H Cl 1.20^(a) 457 220

H Cl 1.23^(a) 485 221

H Cl 1.35^(a) 457 222

H Et 1.20^(a) 451 223

H Et 1.45^(a) 479 224

H Et 1.45^(a) 479

Examples 225-263 3-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

[0270]

[0271] Compounds of formula (lal) were prepared, wherein Rl₀ and R₁₁,have the values listed in Table 10, with the following method (Automatedparallel synthesis).

[0272] A mixture of 1 eq. of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-chloromethyl-6-cyanoquinolineand 3 eq. of an appropriate amine in THF was reacted for overnight atRT. The reaction mixture was filtered and the filtrate was concentrated.The residue was dissolved in CH₂Cl₂ and washed with H₂O, then dried.Removal of the solvent gives the product. TABLE 11 HPLC Ex. retentionNo. —NR₁₀R₁₁ time (min.) MH⁺ 225

2.54 407 226

2.65 421 227

2.82 435 228

2.99 420 229

2.42 411 230

2.83 438 231

2.4 393 232

2.46 407 233

2.92 423 234

3.18 438 235

2.76 435 236

2.48 395 237

2.42 411 238

2.99 437 239

2.73 423 240

2.8 423 241

3.28 435 242

2.84 423 243

2.44 381 244

2.5 410 245

2.4 397 246

3.07 437 247

2.91 423 248

2.55 395 249

2.44 395 250

2.55 409 251

2.64 409 252

2.56 406 253

3 423 254

2.65 425 255

2.54 409 256

3.09 437 257

2.44 411 258

2.43 410 259

2.61 409 260

2.61 409 261

2.64 437 262

2.71 425 263

2.63 437

Examples 264-266 3-(N-acylaminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

[0273]

[0274] Compounds of formula (lam) were prepared, wherein R₁₂ has thevalues in Table 12, below. To a mixture of acyl chloride andtriethylamine in CH₂Cl₂ was added a solution of3-aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile(i.e., Example 192) in dioxane. The reaction mixture was stirred at RTfor 1 h. Then the mixture was diluted with EtOAc and washed with waterbrine and dried (MaSO₄). The solvent was removed under reduced pressureand the residue was subjected to flash column chromatography (silicagel, CH₂Cl₂ /MeOH, 10:1) to give the compounds of Table 12. TABLE 12HPLC Ex. retention No. R₁₂ time (min.) MH⁺ 264

2.76 457 265

3.00 463 266

2.50 458

Examples 267-283 3-Alkoxymethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]quinolines

[0275]

[0276] Compounds of formula (lan) were prepared, wherein R₂, R₆ R₈, andR₉ have the values listed in Table 13, with the following method.

[0277] To 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-bromoquinoline was added SOCl₂,and the resultingreaction solution was stirred at RT under nitrogen for 30 minutes. TheSOCl₂ was then evaporated under reduced pressure, and the residue wasleft overnight under high vacuum. The yellow residue was redissolved inanhydrous DMF, and this solution was then added to a solution ofappropriate alcohol in anhydrous THF (or the yellow residue was treateddirectly with an appropriate Iiquid alcohol). The resulting reactionsolution was stirred for 6 hours at elevated temperature, by which timeHPLC showed the reaction to be complete. After evaporating the solvent,the crude product was chromatographed to yield the title compound. TABLE13 HPLC Ex. retention No. —R₉ R₂ R₆ R₈ time (min.) MH⁺ 267

H CN Et 1.69^(a) 424 268 —CH₃ H CN Et 3.10 396 269

H CN Et 3.35 466 270

H CN Et 3.42 424 271

H CN Et 3.29 410 272

H CN Et 1.60^(a) 454 273

H CN Et 1.39^(a) 426 274

H CN Et 3.91 565 275

H CN Et 3.91 565 276

H CN Et 3.80 551 277

H Br H 2.78 435 278

Cl CN H 2.13^(a) 571 279

Cl CN Et 2.37^(a) 599 280 CH₃ H Br ClCH₂ 3.55 469 281

H Br ClCH₂ 3.78 497 282

H CN Et 3.18 438 283 CH₃ H CN ClCH₂ 3.17 439

Examples 284-2884-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitriles

[0278]

[0279] Compounds of formula (lao) were prepared, wherein R₂ and X₁ havelisted in Table 14, with the methods set forth below.

[0280] Example 284: Example 275 was treated with TFA/CH₂Cl₂ (1:1) for 2hours. the reaction mixture was concentrated. The residue was treatedwith NaHCO₃ (aq. 10%) and extracted with CH₂Cl₂. The combined extractswere dried (NaSO₄) and the solvent was removed. The residue was thenpurified by preparative HPLC to give Example 284.

[0281] Example 285: The same method as Example 285 was used, startingwith Example 279.

[0282] Example 286: To a solution of Example 284 (30 mg) in THF wasadded triethylamine (28 μL) which was followed by CH₃I (4.5 ,L). Theresultant mixture was stirred at RT for overnight. The solvent wasremoved and the residue was chromatographed (silica gel, CH₃OH/CHCl₃,1:9) to give Example 286 (5.1 mg).

[0283] Examples 287 & 288: To a solution of 0.127 mmole of Example 284and 1.27 mmole of the ketone in 0.5 mL of methanol cooled in an ice bathwas added 0.635 mmole of sodium cyanoborohydride. The ice bath wasremoved and the suspension stirred for 4 hours to 2 days. The solutionwas acidified with concentrated HCl and allowed to stir for a fewminutes. The solution was neutralized with concentrated NH₄OH andextracted with methylene chloride. The organic layer was dried overMgSO₄ and filtered, and the filtrate concentrated. The residue waschromatographed on silica gel eluted with methylene chloride/methanol;95:5 and 9:1 to give Examples 287 and 288. TABLE 14 HPLC retention Ex.No. R₂ X₁ time (min) MH⁺ 284 H H 1.27^(a) 465 285 Cl H 1.83^(a) 499 286H —CH₃ 1.27^(a) 479 287 H

2.72 533 288 H —CH(CH₃)₂ 2.57 507

Examples 289-2968-Aminomethyl-3-alkoxymethyl-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]quinolines

[0284]

[0285] Compounds having the formula (lap) were prepared, wherein R₆, R₉,R₁₃ and R₁₄ have the values listed in Table 15. A solution of 0.072mmole of 8-chloromethyl quinoline and 0.072 mmole of amine in 0.5 mL ofTHF was stirred at RT for 16 hours. Another 0.144 mmole of amine wereadded to the incompleted reactions and the solution stirred for 24hours. The solution was diluted with water and extracted with ethylacetate. The organic layer was washed with water, dried over MgSO₄, andfiltered, and the filtrate was concentrated. The residue waschromatographed on silica gel eluted with methylene chloride/methanol;98:2, 95:5 followed by methylene chloride/methanol/NH₄0H; 90:9:1, togive the products. TABLE 15 HPLC retention time Ex. # —R₉ R₆ —NR₁₃R₁₄(min.) MH⁺ 289 —CH(CH₃)₂ Br

1.54^(a) 506 290 —CH(CH₃)₂ Br —NHCH₃ 1.47^(a) 492 291 —CH₃ CN

2.81 425 292 —CH₃ CN

2.15 480 293 —CH₃ CN

1.60 4.68 294 —CH₃ CN

2.30 508 295 —CH₃ CN

1.62 494 296 —CH₃ CN

1.62 508

Examples 297-2993-Alkoxymethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitriles

[0286]

[0287] Compounds having the formula (laq) were prepared, wherein R₉ iscomprising CH₂CH(OH)CH₂NR₁₀R₁₁ and R₁₀ and R₁₁ have the values listed inTable 16. A solution of 0.11 mmole of Example 282 and he appropriateamine in 1 mL of propanol was heated at 60-70° C. for 45 minutes to 30hours. The solution was concentrated and the residue chromatographed(silica gel, methylene chloride/methanol; 95:5, 9:1 and 4:1) to give theproducts. TABLE 16 HPLC Ex. retention No. —NR₁₀R₁₁ time (min.) MH⁺ 297

2.51 509 298

2.67 539 299

2.48 483

Example 3003-[[3-[Bis(1-methylethyl)amino]-2-methoxypropoxy]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile

[0288]

[0289] To 0.069 mmole of Example 298 in 0.5ml of DMF cooled in an icebath was added 0.072 mmole of 60% NaH in mineral oil. The ice bath wasremoved, the suspension stirred for 90 minutes, and 0.076 mmole ofiodomethane were added. The solution was stirred at RT for 16 hours. Anadditional 0.038 mmole of 60% NaH in mineral oil and 0.038 mmole ofiodomethane were added and the solution stirred for 4 hours. Thesolution was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and saturated NaCl solution, driedover MgSO₄ and filtered, and the filtrate concentrated. The residue waschromatographed on silica gel eluted with methylene chloride/methanol;95:5 to give 19 mg of the title compound as a colorless oil. MH₊: 553;LC: 3.21′.

Examples 301 and 302[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]propanedioicacid dialkyl ester

[0290]

[0291] Compounds having the formula (lar) were prepared, wherein R₈ andR₉ have the values listed in Table 17. To a dry clean reaction flask wascharged 1.3 g (33 mmole) of sodium hydride (60% in mineral oil ) and 160ml of dry THF. To this mixture was added dropwise 6.5 g (30 mmole) ofdi-t-butylmalonate over a period of 20 minutes at RT. After completionof the addition, the reaction mixture was stirred at RT for anadditional 15 minutes then cooled to −78° C. A solution of the3-chloromethyl quinoline (˜10 mmole) in 160 ml of DMF was added via anaddition funnel over a period of 1 hour. After completion of theaddition, the reaction mixture was stirred at -78° C. for one more hourthen was quenched with water at 0° C. THF was removed under reducedpressure. The resulting solution was diluted with ethyl ether washedwith water three times, brine, dried over sodium sulfate, andconcentrated, and then purified by column chromatograph (silica gelCH₂Cl₂ /MeOH, 100: 5) to give the product (2.75 g). TABLE 17 HPLCretention Ex. No. R₈ R₉ time (min.) MH⁺ 301 H t-butyl 3.19 552 302 Et Me3.22 496

Example 303 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanoic acid

[0292]

[0293] Example 301 (200mg) was dissolved in 10 ml of ethanol. 1 ml of10% LiOH/H₂O aqueous solution was added. The reaction solution wasstirred at 45° C. for 2 hours. Ethanol was removed under reducedpressure. The resulting aqueous solution was adjusted to pH═4 with 10%HCl. The solid was collected by filtration, rinsed with water, dried toafford 160mg slightly yellow solid. This product (300 mg ) was mixed in0.3 ml of DMF and stirred at 130° C. for 10 minutes. The reactionmixture was cooled to room temperature. Water was added. The solid wascollected by filtration, rinsed with water, and dried to afford 244 mgof the title compound. LC: 2.20′ , MH₊: 396

[0294] Examples 304-306

1-[(3-Chloro-4-methoxyphenyl)methyl]1,2,3,4-tetrahydro-2-oxobenzo[h]1,6-naphthyridine-9-carbonitriles

[0295]

[0296] Compounds having the formula (las) wherein R₈ and X₂ have thevalues listed in Table 18, were prepared as follows.

[0297] Examples 304-305: To a suspension of NaH (123 mg) in THF (10 mL)was added dimethylmalonate (370 mg) dropwise. The mixture was stirred atRT for 15 min. then cooled to −78° C. A solution of4-(3-chloro-4-methoxyphenylmethylamino)-3-chloromethyl-6-cyanoquinoline(0.85 mmol) in DMF was then added dropwise. The reaction was quenched atlow temperature and diluted with Et₂O then washed with water. The etherlayer was concentrated and the residue was purified by flash column(silica gel, CH₂Cl₂ /MeOH, 100:4) to give example 303 (160 mg).

[0298] Example 306: A mixture of the compound of Example 305 (20 mg), 1-isopropylpypirizine (13 mg), EDAC•HCl (20 mg), HOBT•H₂O (15 mg) andDMAP (trace) in pyridine (1.5 mL) was stirred at RT for over night. Thecrude product was purified by preparative HPLC to give Example 306.TABLE 18 HPLC retention Ex. No. R₈ -X₂ time (min.) MH⁺ 304 H —(C═O)OCH₃2.91 436 305 Et —(C═O)OCH₃ 4.04 464 306 H H 2.79 378

Examples 307-3144-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-alkyl-3-quinolinepropanamides

[0299]

[0300] Compounds of formula (lat) wherein R₁₀ and R₁₁, have the valueslisted in Table 19, were prepared as follows.

[0301] The compound of Example 303 (20 mg, 0.05mmole) was mixed with BOPreagent (44 mg, 0.1 mmole ) in 3ml of pyridine and stirred at RT for 3hours. The resulting reaction mixture was purified by preparative HPLCto afford a cream-colored solid. TABLE 19 HPLC Ex. retention No.—NR₁₀R₁₁ time (min.) MH⁺ 307

2.16 486 308 NH₃ 2.08 395 309

2.22 478 310

2.34 423 311

2.14 506 312

2.66 463 313

2.91 477 314

2.71 463

Example 3156-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-2-(2-pyridinyl)−4-quinolinamine

[0302]

[0303] To a suspension of 6-bromo2-(2-pyridine)quinoline-3-aminotbutylester (preparation 28) (300 mg) in DMF (10 mL) was added a solution ofHMDSNa in THF (1M, 0.9 mL) at RT to generate a brown solution. Then 3-chloro-4-methoxybenzyl chloride (160 mg) was added. The reactionmixture was stirred at RT for 2 h. An additional solution of HMDSNa inTHF (0.9 mL) and 3-chloro-4-methoxybenzyl chloride (2 eq) was added andcontinue to stir. When the starting material was consumed, the reactionmixture was treated with TFA. Removal of the solvent and the residue wasredissolved in EtOAc and washed with 1 N NaOH and water. Removal of thesolvent and tritrated with Et₂O to give the title compound (163 mg) as aIight yellow solid. LC: 1.73′MH⁺: 454.

What is claimed is:
 1. A compound of the formula (I):

or a pharmaceutically-acceptable salt thereof, wherein: R₂, R₆, R₇ andR₈ are independently hydrogen, halogen, alkyl, substituted alkyl,alkoxy, nitro, cyano, aryl, heteroaryl, or heterocyclo; R₃ is—(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3; R₄ and R₅ (i) are independentlyhydrogen, alkyl, substituted alkyl, cycloalykl, substituted cycloalkyl,aryl, or heteroaryl, with the proviso that R₄ and R₅ are not bothhydrogen; (ii) taken together form a heterocyclo ring; or (iii) one ofR₄ and R₅ together with Y forms a heterocyclo ring; Y is (i)independently selected from —OR₉, —CO₂R₉, —CH(CO₂R₉)₂,—O(C═O)NR₁₀R₁₁,—NR₁₀R₁₁ ,—NR₁₀ (C═O)NR₁₁R₁₂ ,—CH[(C═O)NR₁₀R,₁₁]₂,—(C═O)NR₁₀R₁₁,—NR₁₀(C═O)R₁₂, —S(O)_(mR,) ₉—SO₂NR₁₀R₁₁, imidazole, substituted imidazole, triazole, substitutedtriazole, or cyano, or (ii) together with R₄or R₅ forms a heterocyloring; and m is 0, 1, or2; R₉ is hydrogen, alkyl, substituted alkyl,hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl,heteroaryl, or pentafluorophenyl; and R₁₀, R₁₁, and R₁₂ are (i)independently selected from hydrogen, alkyl, substituted alkyl, alkoxy,cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl;or (ii) taken together, wherein R₁₀ forms a three-to seven-memberedheterocyclo ring with R₁₁ or R₁₂, or R₁₁, forms a three-toseven-membered heterocyclo ring with R₁₂
 2. A compound of claim 1 or apharmaceutically-acceptable salt thereof, wherein: R₂ is hydrogen,halogen, lower alkyl, or heteroaryl; R₄ is hydrogen, lower alkyl, orforms a heterocyclo ring with Y; R₅ is substituted alkyl having at leastone substitutent that is aryl, cycloalkyl, or heteroaryl; R₆ ishydrogen, halogen, trifluoromethyl, or cyano; R₇ is hydrogen ortrifluoromethyl; R₈ is hydrogen, lower alkyl, or substituted alkylhaving at least one substituent that is —(CH₂)_(n)NR₁₃,R₁₄, wherein R₁₃and R₁₄ (i) are independently selected from hydrogen, alkyl, andsubstituted alkyl, or (ii) taken together form a heterocylco ring; n is0, 1, 2, or 3; Y is (i) —OR₉, —CO₂R₉, —CH(CO₂R₉) ₂,—OR₉NR₁₀R₁₁,—NR₁₀R₁₁, —(C═O)NR₁₀R₁₁ , or —NR₁₀,(C═O)R₁₂ or (ii) together withR₄forms a heterocylo ring; R₉ is hydrogen, alkyl, substituted alkyl,alkoxy, heterocyclo, or pentafluorophenyl; R₁₀ and R₁₁ are (i)independently selected from hydrogen, alkyl, substituted alkyl, alkoxy,cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl;or (ii) taken together wherein R₁₀ and R₁₁, forms a three-toseven-membered heterocyclo ring; and R₁₂is aryl, cycloalkyl, orheteroaryl.
 3. A compound of claim 1 or a pharmaceutically-acceptablesalt thereof, wherein: R₂ is hydrogen or chloro; R₄ is hydrogen; R₅ is3-chloro-4-methoxyphenylmethyl; R₆ is cyano; R₇ is hydrogen; and R₈ ishydrogen, alkyl or substituted alkyl.
 4. A compound of claim 1 or apharmaceutically-acceptable salt thereof, wherein R₄ is hydrogen orlower alkyl, and R₅ is an alkyl substituted with cycloalkyl or aryl. 5.A compound of claim 1 or a pharmaceutically-acceptable salt thereof, inwhich R₅ is a substituted alkyl having a mono-or di-substituted arylgroup in which at least one of the aryl substituents is selected fromhalogen and methoxy.
 6. A compound of claim 5 or apharmaceutically-acceptable salt thereof, wherein R₅ is3-chloro-4-methoxyphenylmethyl.
 7. A compound of claim 1 or apharmaceutically-acceptable salt thereof, wherein Y is (i) —OR₉,—CO₂R₉,—CH(CO₂R₉) ₂,—OR₉R₁₀NR₁₁R₁₁, —(C═O)NR₁₀R₁₁ or —NR₁₀(C═O)R₁₂, or (ii)together with R₄ forms a heterocylo ring.
 8. A compound of claim 1 or apharmaceutically-acceptable salt thereof, wherein Y is CO₂R₉, and R₉ ishydrogen, lower alkyl, alkoxy, or substituted alkyl having at least onesubstituent that is a heterocyclo group, wherein when said heterocyclogroup has the heteroatom N, said heteroatom N is substituted with agroup X₁ selected from alkyl, substituted alkyl, and cycloalkyl.
 9. Acompound of claim 1 or a pharmaceutically-acceptable salt thereof,wherein R₃ is (CH₂)_(z)NR₁₀R₁₁, (C═O)NR₁₀R₁₁or (CH₂)_(z)NR₉R₁₀ R₁₁; R₉is alkoxy having from 1 to 4 carbon atoms, said alkoxy having asubstituent selected from hydroxy and alkoxy; and R₁₀ and R₁₁ are (i)independently hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy, orheterocyclo, or (ii) together form a heterocylco ring.
 10. The compoundof claim 1, wherein z is zero, R₃ is OR₉and R₉ is hydrogen or loweralkyl.
 11. The compound of claim 1, wherein R₆ is cyano.
 12. Thecompound of claim 1, selected from (i)4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-7-triflouromethyl-3-quinolinecarboxylicacid ethyl ester;6-bromo-2-chloro-4-[[(4-fluorophenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester; 6-bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-triflouromethyl-3-quinolinecarboxylicacid ethyl ester; (S)-6-cyano-4-[(1-cyclohexylethyl)amino]-3-quinolinecarboxylic acid ethyl ester;(R)-6-cyano-4-[(1-cyclohexylethyl)amino]-3-quinolinecarboxylic acidethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-fluoro-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-propoxycarbonyl-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-methoxycarbonyl-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid ethyl ester;8-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid ethyl ester;8-acetoxymethyl-6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-methyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chlorophenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-4-[[(3,4-dichlorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-4-[[(2,3-dichlorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[[(4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;(S)-6-cyano-4-[(1-cyclohexylethyl)amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;(R)-6-cyano-4-[(1-cyclohexylethyl)amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-propoxycarbonyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-methoxycarbonyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethoxycarbony-3-lquinolinecarboxylicacid ethyl ester; 6-cyano-8-ethyl-4-furfurylamino-3-quinolinecarboxylicacid ethyl ester; 6-cyano-8-ethyl-4-piperonylamino-3-quinolinecarboxylicacid ethyl ester; 6-cyano-8-ethyl-4-[[(3-trifluoromethylphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(3,4-difluorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(4-trifluoromethylphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(4-isopropylphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;4-[[(4-t-butylphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid ethyl ester; 6-cyano-4-[[(3,5-dichlorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(2,5-dimethoxyphenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(3,5-dimethoxyphenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(4-trifluoromethoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(2,6-dichlorophenyl)ethyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(3,4,5-trimethoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(2-fluoro-4-trifluoromethylphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[[4-(1,2,3 -thiadiazol-4-yl)phenyl]methyl]amino]-3-quinolinecarboxylic acid ethyl ester;(S)-6-cyano-8-ethyl-4-[(1-phenylethyl)amino ]-3-quinolinecarboxylic acidethyl ester; (R)-6-cyano-8-ethyl-4-[(1-phenylethyl)amino]-3-quinolinecarboxylic acid ethyl ester;(S)-4-[[1-(4-bromophenyl)ethyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid ethyl ester;(R)-4-[[1-(4-bromophenyl)ethyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid ethyl ester;(S)-6-cyano-8-ethyl-4-[[1-(4-methylphenyl)ethyl]amino]-3-quinolinecarboxylic acid ethyl ester;(S)-6-cyano-8-ethyl-4-[[1-(4-methylphenyl)ethyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[(phenylmethyl)amino]-3-quinolinecarboxylic acid ethylester; 4-[[(4-bromophenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(4-methylphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester; 6-cyano-4-[[(4-difluoromethoxyphenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(4-methylthiolphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester; 6-Cyano-4-[[(2,3-dihydro-1H-inden-2-yl)methyl]amino ]-8-ethyl-3-quinolinecarboxylic acid ethylester; 6-cyano-4-[[(4-dichlorophenyl)ethyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(3,5-dimethoxyphenyl)ethyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(3-ethoxy−4-methoxyphenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;4-[[(5-chloro-2-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-hydroxymethyl-3-quinolinecarboxylic acid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-chloromethyl-3-quinolinecarboxylic acid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino)]-8-dimethylaminomethyl-3-quinolinecarboxylic acid ethylester; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylic acid; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-7-trifluoromethyl-3-quinolinecarboxylic acid;6-bromo-2-chloro-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-fluoro-3-quinolinecarboxylic acid; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid; 8chloro-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylic acid;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid pentafluorophenyl ester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid pentafluorophenyl ester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-(4-pyridinylmethyl)-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-[2-(4-pyridinyl)ethyl]-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-[2-(4-morpholinyl)ethyl]-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-(4-hydroxybutyl)-7-(trifluoromethyl)-3-quinolinecarboxamide;trans-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-(4-hydroxycyclohexyl)-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-ethyl-7-(trifluoromethyl)-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-7-(trifluoromethyl)-3-quinolinyl]carbonyl]-4-piperidinol;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-pyridinylmethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(4-morpholinyl)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(4-methyl-1-piperazinyl)propyl]-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-methylpiperazine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N,N-diethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(dimethylamino)ethyl]-3-quinolinecarboxamide;N-(2-Aminoethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-20 quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-hydroxy−2-(4-hydroxyphenyl)ethyl]-3-quinolinecarboxamide; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(hexahydro-2-oxo-1 H-azepin-3-yl)-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl) methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-ethylpiperazine; 1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl ]-4-cyclopentylpiperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(2-methoxyethyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(1-pyrrolidinyl)piperidine; 1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyi]-4,1 ′ -bipiperidine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]carbonyl]-4-cyclopentylpiperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl ]amino]-6-cyano-8-ethyl-3-quinolinyl]carbonyl]-4-(1-methylethyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl) methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(1-methylethyl)piperazine;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-ethylpiperazine;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-(1-methylethyl)piperazine;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-cyclopentylpiperazine;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl) methyl]amino]-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-methylpiperazine;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(dimethylamino)propyl]-3-quinolinecarboxamide;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(4-methyl-1-piperazinyl)propyl]-3-quinolinecarboxamide;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(4-morpholinyl)propyl]-3-quinolinecarboxamide;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-quinolinecarboxamide;2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]pyrrolidine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-2-(1-pyrrolidinylmethyl)pyrrolidine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N,N-dimethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-methyl-N-propyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-cyclopentyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-hexyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-ethoxyethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(2-hydroxyethoxy)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(3-methoxypropyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(3-propoxypropyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[(tetrahydro-2-furanyl)methyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-hydroxyethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(3-hydroxypropyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-hydroxybutyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(5-hydroxypentyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[1-(hydroxymethyl)butyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-hydroxyethyl)-N-propyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N,N-bis(2-hydroxyethyl)-3-quinolinecarboxamide;trans-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-hydroxycyclohexyl)-3-quinolinecarboxamide;3-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]amino]propanoicacid methyl ester; 4-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]amino]butanoic acid methyl ester;N-[2-(Acetylamino)ethyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(2-oxo−1-pyrrolidinyl)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(diethylamino)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(dimethylamino)ethyl]-N-ethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(diethylamino)ethyl]-N-methyl-3-quinolinecarboxamide;N-[2-(Butylethylamino)ethyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(1-pyrrolidinyl)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(1-piperidinyl)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6 -cyano-N-ethyl-N-(l-ethyl-3-pyrrolidinyl)-3-quinolinecarboxamide;N-(3-Aminopropyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;N-(3-Amino-2-hydroxypropyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide; N-(3-Amino-2,2-dimethylpropyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(dimethylamino)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(diethylamino)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(diethylamino)propyl]-N-methyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(2-methyl-1-piperidinyl)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6 -cyano-N-methyl-N-(l-methyl-4-piperidinyl)-3-quinolinecarboxamide;4-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]amino]-1-piperidinecarboxylic acid ethylester; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[1-(phenylmethyl)-4-piperidinyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(methylphenylamino)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[4-(dimethylamino)butyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[6-(dimethylamino)hexyl]-3-quinolinecarboxamide;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]morpholine;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]thiomorpholine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-morpholinyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(4-morpholinyl)propyl]-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-pyrrolidinol;N-[1-[[4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-pyrrolidinyl]acetamide;(R)-1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-N,N-dimethyl-3-pyrrolidinamine; 1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]piperidine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-piperidinol;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-piperidineethanol;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-piperidinecarboxylic acid ethylester; 1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-piperidinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-piperidinecarboxamide;8-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-1,4-dioxa-8-azaspiro[4.5]decane;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]piperazine;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-N,N-dimethyl-1-piperazinepropanamine;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-1-piperazineethanol;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-cyclohexylpiperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(2-pyridinyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(2-pyrimidinyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]hexahydro-1H-1,4-diazepine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]hexahydro-4-methyl-1H-1,4-diazepine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(phenylmethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(3-pyridinylmethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(4-hydroxyphenyl)ethyl]-3-quinolinecarboxamide;N-(1,3-Benzodioxol-5-ylmethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;6-Bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3quinolinemethanol;8Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile;(S)-4-[(1-Cyclohexylethyl)amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;(R)-4-[(1-Cyclohexylethyl)amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3,4-Dichlorophenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(2,3-Dichlorophenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chlorophenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(4-methoxyphenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3,8-bis(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(4-methyl-1-piperazinyl)methyl]-6-quinolinecarbonitrile;3-(Aminomethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-pyridinylmethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(1-piperidinylmethyl)-6-quinolinecarbonitrile;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-3-[(4-methyl-1-piperazinyl)methyl]-4-quinolinamine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(dipropylamino)methyl]-6-quinolinecarbonitrile;3-[[Bis(2-methylpropyl)amino]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile;2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-[(3-hydroxy-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(dimethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclohexylmethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(3-methyl-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2S)-2-(methoxymethyl)-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(3R)-3-hydroxy-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[4-(hydroxymethyl)-1-piperidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(2-methyl-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclopentylmethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(3-hydroxy−1-pyrrolidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(2-ethyl-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[2-(hydroxymethyl)-1-piperidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(3-hydroxy−1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[(4-chlorophenyl)methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[(4-fluorophenyl)methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[(4-methoxyphenyl)methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(3-hydroxy-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(phenylmethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;8-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-[[(3R)-3-hydroxy-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;8-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-[[4-(hydroxymethyl)-1-piperidinyl]methyl]-6-quinolinecarbonitrile;8-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(4-morpholinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(3R)-3-hydroxy-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;(2R)-2-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methyl]-2-pyrrolidinecarboxylicacid; (2S)-2-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methyl]-2-pyrrolidinecarboxylic acid;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclobutylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclopentylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclohexylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-cyanoethyl)methylamino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxyethyl)methylamino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxyethyl)propylamino]methyl]-6-quinolinecarbonitrile;3-(1-Azetidinylmethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(1-pyrrolidinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(4-morpholinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chioro-4-methoxyphenyl)methyl]amino]-3-(4-thiomorpholinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(hexahydro-1H-azepin-1-yl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1-methylethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxy-1-methylethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1,3-dimethylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1-ethylpropyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1-methylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2,2,2-trifluoroethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]3-[[(2,2-dimethylpropyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(ethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-methoxyethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxyethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(3,3-dimethylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(3-methylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(propylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(ethylmethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(diethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(methylpropylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-cyanoethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[methyl(2-methylpropyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-ethoxyethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[methyl(1-methylethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[methyl(3-methylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[( 1R)-1-methylpropyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[[(2S)-tetrahydro-2-furanyl]methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-methoxyethyl)methylamino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[[(2R)-tetrahydro-2-furanyl]methyl]amino]methyl]-6-quinolinecarbonitrile;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]benzamide;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]cyclohexanecarboxamide;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]-2-pyridinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(propoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(tetrahydro-2-furanyl)methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(1-methylethoxy)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(ethoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(2-ethoxyethoxy)methyl]-8-ethyl-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(2-hydroxyethoxy)methyl]-6-quinolinecarbonitrile;(2R)-2-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylic acid1,1-dimethylethyl ester;(2S)-2-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylic acid1,1-dimethylethyl ester;(3R)-3-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]-1-pyrrolidinecarboxylic acid1,1-dimethylethyl ester;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-3-(ethoxymethyl)-4-quinolinamine;(2S)-2-[[[2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylic acid1,1-dimethylethyl ester;(2S)-2-[[[2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylicacid 1,1-dimethylethyl ester;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-8-(chloromethyl)-3-(methoxymethyl)-4-quinolinamine;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-8-(chloromethyl)-3-[(1-methylethoxy)methyl]-4-quinolinamine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(oxiranylmethoxy)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-(chloromethyl)-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(2S)-2-pyrrolidinylmethoxy]methyl]-6-quinolinecarbonitrile;2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]8-ethyl-3-[[(2S)-2-pyrrolidinylmethoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-1-methyl-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-1-cyclopentyl-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-I-(1-methylethyl)-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;6-Bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N, N-dimethyl-3-[(l-methylethoxy)methyl]-8-quinolinemethamine;6-Bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-methyl-3-[(1-methylethoxy)methyl]-8-quinolinemethamine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[(dimethylamino)methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[(4-methyl-1-piperazinyl)methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[[(dimethylaminoethyl)amino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8 -[[(l-methyl-4-piperidinyl)methylamino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[[(1-pyrrolidinylethyl)amino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8 -[[(l-ethyl-2-pyrrolidinylmethyl)amino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[2-hydroxy-3-(-pyrrolidinyl)propoxy]methyl]-6-quinolinecarbonitrile;3-[[3-[Bis(1-methylethyl)amino]-2-hydroxypropoxy]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[3-(dimethylamino)-2-hydroxypropoxy]methyl]-8-ethyl-6-quinolinecarbonitrile;3-[[3-[Bis(1-methylethyl)amino]-2-methoxypropoxy]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile; [[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]propanedioic acid bis(1,1-dimethylethyl)ester;[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methyl]propanedioicacid dimethyl ester; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanoic acid;1-[(3-Chloro-4-methoxyphenyl)methyl]-9-cyano-1,2,3,4-tetrahydro-2-oxobenzo[h]-1,6-naphthyridine-3-carboxylic acid methylester; 1-[(3-Chloro-4-methoxyphenyl)methyl]-9-cyano-7 -ethyl-1,2,3,4-tetrahydro-2-oxobenzo[h]-1,6-naphthyridine-3-carboxylic acid methylester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanoicacid; 1-[(3-Chloro-4-methoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-oxobenzo[h]-1,6-naphthyridine-9-carbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-pyridinylmethyl)-quinolinepropanamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanamide;1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]-oxopropyl]-4-methylpiperazine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-ethyl-3-quinolinepropanamide;1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyi]1-oxopropyl]-4-(1-methylethyl)piperazine;1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]-1oxopropyl]piperidine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-cyclohexyl-3-quinolinepropanamide; and4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-cyclopentyl-3-quinolinepropanamide; and (ii) apharmaceutically-acceptable salt thereof.
 13. The compound of claim 1selected from (i)4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-30 methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(3R)-3-hydroxy-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]benzamide;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]cyclohexanecarboxamide;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]-2-pyridinecarboxamide; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(propoxymethyl)-6-quinolinecarbonitrile; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(methoxymethyl)-6-quinolinecarbonitrile; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(tetrahydro-2-furanyl)methoxy]methyl]-6-quinolinecarbonitrile; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(1-methylethoxy)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(ethoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(2-ethoxyethoxy)methyl]-8-ethyl-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(2-hydroxyethoxy)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(oxiranylmethoxy)methyl]-6-quinolinecarbonitrile; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-1-methyl-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-1-cyclopentyl-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[2-hydroxy-3-(1-pyrroIid inyl)propoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[3-(dimethylamino)-2-hydroxypropoxy]methyl]-8-ethyl-6-quinolinecarbonitrile;[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methyl]propanedioicacid dimethyl ester; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-ethyl-3-quinolinepropanamide; 1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]-1-oxopropyl]-4-(1-methylethyl)piperazine;1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinoinyl]-1-oxopropyl]piperidine,trifluoroacetate; and4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-cyclopentyl-3-quinolinepropanamide;and (ii) a pharmaceutically-acceptable salt thereof.
 14. Apharmaceutical composition adapted for treating a cGMP-associatedcondition comprising (a) one or more compounds of the formula (I),

or a pharmaceutically acceptable salt thereof, and (b) apharmaceutically acceptable carrier or diluent, wherein: R₂, R₆, R₇ andR₈are independently hydrogen, halogen, alkyl, substituted alkyl, alkoxy,nitro, cyano, aryl, or heteroaryl; R₃ is hydrogen or —(CH₂)_(z)Y whereinz is 0, 1, 2, or 3; R₄ and R₅ (i) are independently hydrogen, alkyl,substituted alkyl, cycloalykl, substituted cycloalkyl, aryl, orheteroaryl, with the proviso that R₄ and R₅ are not both hydrogen; or(ii) taken together form a heterocyclo ring; or (iii) one of R₄ andR₅together with Y forms a heterocyclo ring; Y is selected (i)independently from —OR₉, —CO₂R₉, —CH(CO₂R₉)₂, —O(C═O)NR₁₀ R₁₁,—NR₁₀R₁₁₁,—NR₁₀(C═O)NR₁₁R₁₂, —CH[(C═O)NR₁₀,R₁₁]₂ ,-(C═O)NR₁₀R₁₁,—NR₁₀(C═O)R₁₂,—S(O)_(m)R₉, —SO₂NR₁₀R₁₁, imidazole, substituted imidazole, triazole,substituted triazole, and cyano, or (ii) together with R₄or R₅, forminga heterocylo ring therewith; m is 0, 1, or 2; R₉ is hydrogen, alkyl,substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl,heterocyclo, aryl, heteroaryl, or pentafluorophenyl; and R₁₀, R₁₁, andR₁₂ (i) are independently selected from hydrogen, alkyl, substitutedalkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo,and heteroaryl; or (ii) taken together wherein R₁₀ forms a three-toseven-membered heterocyclo ring with R₁₁, or R₁₂, or R₁₁, forms athree-to seven-membered heterocyclo ring with R₁₂.
 15. Thepharmaceutical composition of claim 14, wherein: R₂ is hydrogen orchloro; R₃ is —(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3; R₄ is hydrogen;R₅ is 3-chloro-4-methoxyphenylmethyl; R₆ is cyano; R₇ is hydrogen; andR₈ is hydrogen, alkyl or substituted alkyl.
 16. The pharmaceuticalcomposition of claim 14, in which the one or more compounds of formula(I) are selected from: (i) 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylic acid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-7-triflouromethyl-3-quinolinecarboxylic acid ethyl ester;6-bromo-2-chloro-4-[[(4-fluorophenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;6-bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-triflouromethyl-3-quinolinecarboxylic acid ethyl ester;(S)-6-cyano-4-[(1-cyclohexylethyl)amino]-3-quinolinecarboxylic acidethyl ester;(R)-6-cyano-4-[(1-cyclohexylethyl)amino]-3-quinolinecarboxylic acidethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-fluoro-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-propoxycarbonyl-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-methoxycarbonyi-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid ethyl ester;8-acetoxymethyl-6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-methyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chlorophenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-4-[[(3,4-dichlorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-4-[[(2,3-dichlorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[[(4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;(S)-6-cyano-4-[(l-cyclohexylethyl)amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;(R)-6-cyano-4-[(1-cyclohexylethyl)amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-propoxycarbonyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-methoxycarbonyl-3-quinolinecarboxylicacid ethyl ester;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethoxycarbony-3-lquinolinecarboxylicacid ethyl ester; 6-cyano-8-ethyl-4-furfurylamino-3-quinolinecarboxylicacid ethyl ester; 6-cyano-8-ethyl-4-piperonylamino-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[[(3-trifluoromethylphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(3,4-difluorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[[(4-trifluoromethylphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(4-isopropylphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester;4-[[(4-t-butylphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-4-[[(3,5-dichlorophenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-4-[[(2,5-dimethoxyphenyl)methyi]amino]-8-ethyl-3-quiolinecarboxylicacid ethyl ester;6-cyano-4-[[(3,5-dimethoxyphenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[[(4-trifluoromethoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-4-[[(2,6-dichlorophenyl)ethyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[[(3,4,5-trimethoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(2-fluoro-4-trifluoromethylphenyl)methyl]amino]-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl]amino]-3-quinolinecarboxylic acid ethyl ester;(S)-6-cyano-8-ethyl-4-[(1-phenylethyl)amino]-3-quinolinecarboxylic acidethyl ester;(R)-6-cyano-8-ethyl-4-[(1-phenylethyl)amino]-3-quinolinecarboxylic acidethyl ester;(S)-4-[[1-(4-bromophenyl)ethyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid ethyl ester; (R)-4-[[l-(4-bromophenyl)ethyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acidethyl ester;(S)-6-cyano-8-ethyl-4-[[1-(4-methylphenyl)ethyl]amino]-3-quinolinecarboxylicacid ethyl ester;(S)-6-cyano-8-ethyl-4-[[1-(4-methylphenyl)ethyl]amino]-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[(phenylmethyl)amino]-3-quinolinecarboxylic acid ethylester;4-[[(4-bromophenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-8-ethyl-4-[[(4-methylphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester; 6-cyano-4-[[(4-difluoromethoxyphenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-cyano-8-ethyl-4-[[(4-methylthiolphenyl)methyl]amino]-3-quinolinecarboxylicacid ethyl ester; 6-Cyano-4-[[(2,3-dihydro-1H-inden-2-yl)methyl]amino]-8 -ethyl-3-quinolinecarboxylic acid ethylester;6-cyano-4-[[(4-dichlorophenyl)ethyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester;6-cyano-4-[[(3,5-dimethoxyphenyl)ethyl]amino]-8-ethyl-3-quinolinecarboxylicacid ethyl ester; 6-cyano-4-[[(3-ethoxy-4-methoxyphenyl)methyl]amino]-8-ethyl-3-quinolinecarboxylic acid ethyl ester;4-[[(5-chloro-2-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-hydroxymethyl-3-quinolinecarboxylic acid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-chloromethyl-3-quinolinecarboxylic acid ethyl ester;6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino)]-8-dimethylaminomethyl-3-quinolinecarboxylic acid ethyl ester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-7-trifluoromethyl-3-quinolinecarboxylic acid;6-bromo-2-chloro-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylic acid;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-fluoro-3-quinolinecarboxylicacid; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid; 8[[(3-chloro-4-methoxyphenyl)methyl]amino]-6 -cyano-3-quinolinecarboxylicacid;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]methylamino]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid pentafluorophenyl ester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid pentafluorophenyl ester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-(4-pyridinylmethyl)-7-(trifluoromethyl)-3-quinolinecarboxamide;.4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-[2-(4-pyridinyl)ethyl]-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro4-methoxyphenyl)methyl]amino]-N-[2-(4-morpholinyl)ethyl]-7-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-(4-hydroxybutyl)-7-(trifluoromethyl)-3-quinolinecarboxamide;trans-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-(4-hydroxycyclohexyl)-(trifluoromethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-N-ethyl-7-(trifluoromethyl)-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-7-(trifluoromethyl)-3-quinolinyl]carbonyl]-4-piperidinol;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-pyridinylmethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(4-morpholinyl)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(4-methyl-1-piperazinyl)propyl]-3-quinolinecarboxamide;1-[[4-[[(3-Chloro4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-methylpiperazine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N,N-diethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(dimethylamino)ethyl]-3-quinolinecarboxamide;N-(2-Aminoethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(hexahydro-2-oxo-1H-azepin-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-ethylpiperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-cyclopentylpiperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(2-methoxyethyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(1-pyrrolidinyl)piperidine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4,1′-bipiperidine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]carbonyl]-4-cyclopentylpiperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]carbonyl]-4-(1-methylethyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(1-methylethyl)piperazine;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-ethylpiperazine;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-(1-methylethyl)piperazine;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-cyclopentylpiperazine;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;1-[[6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinyl]carbonyl]-4-methylpiperazine;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(dimethylamino)propyl]-3-quinolinecarboxamide;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(4-methyl-1-piperazinyl)propyl]-3-quinolinecarboxamide;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(4-morpholinyl)propyl]-3-quinolinecarboxamide;6-Bromo-2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-quinolinecarboxamide;2-chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-pyridinylmethyl)-3-quinolinecarboxamide; 2pyridinylmethyl)-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]pyrrolidine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-2-(1-pyrrolidinylmethyl)pyrrolidine;4-[[3-(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N,N-dimethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-methyl-N-propyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-cyclopentyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-hexyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-ethoxyethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(2-hydroxyethoxy)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(3-methoxypropyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(3-propoxypropyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[(tetrahydro-2-furanyl)methyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-hydroxyethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-eyano-N-(3-hydroxypropyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-hydroxybutyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(5-hydroxypentyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[1-(hydroxymethyl)butyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-hydroxyethyl)-N-propyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N,N-bis(2-hydroxyethyl)-3-quinolinecarboxamide;trans-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-hydroxycyclohexyl)-3-quinolinecarboxamide;3-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]amino]propanoicacid methyl ester; 4-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]amino]butanoic acid methyl ester;N-[2-(Acetylamino)ethyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-12-(diethylamino)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(dimethylamino)ethyl]-N-ethyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(diethylamino)ethyl]-N-methyl-3-quinolinecarboxamide;N-[2-(Butylethylamino)ethyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-1 0 cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(1-pyrrolidinyl)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(1-piperidinyl)ethyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-ethyl-N-(1-ethyl-3-pyrrolidinyl)-3-quinolinecarboxamide;N-(3-Aminopropyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;N-(3-Amino-2-hydroxypropyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;N-(3-Amino-2,2-dimethylpropyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(dimethylamino)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(diethylamino)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(diethylamino)propyl]-N-methyl-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(2-methyl-1-piperidinyl)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6 -cyano-N-methyl-N-(l-methyl-4-piperidinyl)-3-quinolinecarboxamide;4-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]amino]-1-piperidinecarboxylicacid ethyl ester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[1-(phenylmethyl)-4-piperidinyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(methylphenylamino)propyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[4-(dimethylamino)butyl]-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[6-(dimethylamino)hexyl]-3-quinolinecarboxamide;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]morpholine;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]thiomorpholine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(4-morpholinyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[3-(4-morpholinyl)propyl]-3-quinolinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-pyrroIidinol;N-[1-[[4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-pyrrolidinyl]acetamide;(R)-1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-N, N-dimethyl-3-pyrrolidinamine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]piperidine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-piperidinol;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-piperidineethanol;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-piperidinecarboxylicacid ethyl ester; 1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-piperidinecarboxamide;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-3-piperidinecarboxamide;8[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-1,4-dioxa-8-azaspiro[4.5]decane;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]piperazine;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-N,N-dimethyl-1-piperazinepropanamine;4-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-1-piperazineethanol;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-cyclohexylpiperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(2-pyridinyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]-4-(2-pyrimidinyl)piperazine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]hexahydro-1H-1 ,4-diazepine;1-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]carbonyl]hexahydro-4-methyl-1H-1 ,4-diazepine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(phenylmethyl)-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(3-pyridinylmethyl)-3-quinolinecarboxamide;4-[[(3-Chloro4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-pyridinylmethyl)-3-quinolinecarboxamide;4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-[2-(4-hydroxyphenyl)ethyl]-3-quinolinecarboxamide;N-(1,3-Benzodioxol-5-ylmethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;6-Bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinemethanol;8 Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile;(S)-4-[(1-Cyclohexylethyl)amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;(R)-4-[(1-Cyclohexylethyl)amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3,4-Dichlorophenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(2,3-Dichlorophenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chlorophenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(4-methoxyphenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3,8-bis(hydroxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(4-methyl-1-piperazinyl)methyl]-6-quinolinecarbonitrile;3-(Aminomethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-pyridinylmethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(1-piperidinylmethyl)-6-quinolinecarbonitrile;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-3-[(4-methyl-1-piperazinyl)methyl]-4-quinolinamine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(dipropylamino)methyl]-6-quinolinecarbonitrile;3-[[Bis(2-methylpropyl)amino]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile;2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-[(3-hydroxy-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(dimethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclohexylmethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(3-methyl-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(3R)-3-hydroxy-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[4-(hydroxymethyl)-1-piperid inyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(2-methyl-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclopentylmethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(3-hydroxy-1-pyrrolidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(2-ethyl-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[2-(hydroxymethyl)-1-piperidinyl]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(3-hydroxy-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[(4-chlorophenyl)methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[(4-fluorophenyl)methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[(4-methoxyphenyl)methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(3-hydroxy-1-piperidinyl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(phenylmethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;8-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-[[(3R)-3-hydroxy-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;8-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-[[4-(hydroxymethyl)-1-piperid inyl]methyl]-6-quinolinecarbonitrile;4-[[Chloro-4-(3-chloro-4-methoxyphenyl)methyl]amino]-3-(4-morpholinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(3R)-3-hydroxy-1-pyrrolidinyl]methyl]-6-quinolinecarbonitrile;(2R)-2-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methyl]-2-pyrrolidinecarboxylicacid;(2S)-2-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methyl]-2-pyrrolidinecarboxylicacid;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclobutylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclopentylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(cyclohexylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-cyanoethyl)methylamino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxyethyl)methylamino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxyethyl)propylamino]methyl]-6-quinolinecarbonitrile;3-(1-Azetidinylmethyl)-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(1-pyrrolidinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(4-morpholinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(4-thiomorpholinylmethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(hexahyd ro-1H-azepin-1-yl)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1-methylethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxy-1-methylethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1,3-dimethylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1-ethylpropyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(1-methylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2,2,2-trifluoroethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2,2-dimethylpropyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(ethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-methoxyethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-hydroxyethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(3,3-dimethylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(3-methylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(propylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(ethylmethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(diethylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(methylpropylamino)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-cyanoethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[methyl(2-methylpropyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-ethoxyethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[methyl(1-methylethyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[methyl(3-1 0methylbutyl)amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[(1R)-1-methylpropyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[[(2S)-tetrahydro-2-furanyl]methyl]amino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[(2-methoxyethyl)methylamino]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[[[(2R)-tetrahydro-2-furanyl]methyl]amino]methyl]-6-quinolinecarbonitrile;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-20quinolinyl]methyl]benzamide;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]cyclohexanecarboxamide;N-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]-2-pyridinecarboxamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(propoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(tetrahydro-2-furanyl)methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(1-methylethoxy)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(ethoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(2-ethoxyethoxy)methyl]-8-ethyl-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(2-hydroxyethoxy)methyl]-6-quinolinecarbonitrile;(2R)-2-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylicacid 1,1-dimethylethyl ester;(2S)-2-[[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylicacid 1,1-dimethylethyl ester;(3R)-3-[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]-1-pyrrolidinecarboxylicacid 1,1-dimethylethyl ester;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-3-(ethoxymethyl)-4-quinolinamine;(2S)-2-[[[2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylicacid 1,1-dimethylethyl ester;(2S)-2-[[[2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methoxy]methyl]-1-pyrrolidinecarboxylicacid 1,1 -dimethylethyl ester;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-8-(chloromethyl)-3-(methoxymethyl)-4-quinolinamine;6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-8-(chloromethyl)-3-[(1-methylethoxy)methyl]-4-quinolinamine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[(oxiranylmethoxy)methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-(chloromethyl)-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(2S)-2-pyrrolidinylmethoxy]methyl]-6-quinolinecarbonitrile;2-Chloro-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[(2S)-2-pyrrolidinylmethoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-1-methyl-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-1-cyclopentyl-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-1-(1-methylethyl)-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitrile;6-Bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N,N-dimethyl-3-[(1-methylethoxy)methyl]-8-quinolinemethamine;6-Bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-N-methyl-3-[(1-methylethoxy)methyl]-8-quinolinemethamine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[(dimethylamino)methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[(4-methyl-1-piperazinyl)methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[[(dimethylaminoethyl)amino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[[(1-methyl-4-piperidinyl)methylamino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[[(1-pyrrolidinylethyl)amino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-[[(1-ethyl-2-pyrrolidinylmethyl)amino]methyl]-3-(methoxymethyl)-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[2-hydroxy-3-(1-pyrrolidinyl)propoxy]methyl]-6-quinolinecarbonitrile;3-[[3-[Bis(1-methylethyl)amino]-2-hydroxypropoxy]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[[3-(dimethylamino)-2-hydroxypropoxy]methyl]-8-ethyl-6-quinolinecarbonitrile;3-[[3-[Bis(1-methylethyl)amino]-2-methoxypropoxy]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile;[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]propanedioicacid bis(1,1-dimethylethyl) ester;[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinyl]methyl]propanedioicacid dimethyl ester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanoicacid; 1-[(3-Chloro-4-methoxyphenyl)methyl]-9-cyano-1,2,3,4-tetrahydro-2-oxobenzo[h]-1 ,6-naphthyridine-3-carboxylic acid methylester; 1-[(3-Chloro-4-methoxyphenyl)methyl]-9-cyano-7-ethyl-1,2,3,4-tetrahydro-2-oxobenzo[h]-1,6-naphthyridine-3-carboxylic acid methylester;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanoicacid; 1-[(3-Chloro-4-methoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-oxobenzo[h ]-1 ,6-naphthyridine-9-carbonitrile;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-(2-pyridinylmethyl)-3-quinolinepropanamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanamide;1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]-1-oxopropyl]-4-methylpiperazine;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-ethyl-3-quinolinepropanamide;1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]-1-oxopropyl]-4-(1-methylethyl)piperazine;1-[3-[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]-1-oxopropyl]piperidine; 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-cyclohexyl-3-quinolinepropanamide;4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-cyclopentyl-3-quinolinepropanamide; and6-Bromo-N-[(3-chloro-4-methoxyphenyl)methyl]-2-(2-pyridinyl)-4-quinolinamine; and (ii) a pharmaceutically-acceptable saltthereof. `17. A method of treating a cGMP-associated conditioncomprising administering to a mammal in need thereof atherapeutically-effective amount of one or more compounds of claim 1.`18. A method of treating a cGMP-associated condition comprisingadministering to a mammal in need thereof a therapeutically-effectiveamount the composition of claim
 14. `19. The method of claim 17, whereinthe cGMP-associated condition is selected from a cardiovasculardisorder, male or female sexual dysfunction, diabetes mellitus, and agastrointestinal disorder comprising gastric paresis. `20. The method ofclaim 18, wherein the cGMP-associated condition is selected from acardiovascular disorder, male or female sexual dysfunction, diabetesmellitus, and a gastrointestinal disorder comprising gastric paresis.